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Showing 93 of 200 peer-reviewed papers with full Graphical Abstracts.

Original ResearchVol. 16, None • pp. 663DOI: 10.1186/s13287-025-04780-x

Extracellular vesicles from Yiguanjian-primed bone-marrow mesenchymal stem cells ameliorate chronic liver fibrosis via miR-7045-5p

Authors: Zhejun Liu, Xiaodan Jiang, Hongjie You, Zuoqing Tang, Yun Ma, Niancong Che, Chongyang Ma, Wenlan Liu

Background Liver fibrosis is a crucial pathological stage in the progression of chronic liver diseases. Yiguanjian (YGJ), a Chinese herbal formula, exhibits anti-inflammatory, anti-fibrotic, and hepatoprotective effects. Extracellular vesicles from bone-marrow mesenchymal stem cells (BMSC-EVs) have shown potential in treating various disorders, including liver fibrosis. This study investigated the regulatory effects of EVs from YGJ-preconditioned BMSCs (YGJ-EVs) on TGF-β1-stimulated hepatic stellate cells (HSCs) and their therapeutic potential in a mouse model of liver fibrosis, with a focus on identifying the causative microRNA cargo. Methods YGJ-EVs and control EVs were isolated from BMSC culture supernatants and characterized via western blotting, transmission electron microscopy, and nanoparticle tracking analysis. Their cellular uptake in vitro and in vivo was evaluated using DIR labeling. To identify candidate miRNAs mediating YGJ-EV bioactivity, miRNA microarray analysis was conducted. To assess the effect of YGJ-EVs on liver fibrosis, TGF-β1-activated HSC cells were treated with YGJ-EVs or control-EVs for 24 h, and then the expression of proteins related to fibrotic activation (COL1-A1 and α-SMA), lysosomal biogenesis (LAMP1, TPP1, CTSD, and CTSB) mitophagy (p62, LC3, PINK1, and Parkin), and the Akt/AMPK/TFEB pathway was assessed. To determine whether miR-7045-5p is the causative factor, HSC cells transfected with miR-7045-5p were similarly analyzed. Results miRNA microarray analysis revealed miR-7045-5p upregulation in YGJ-EVs versus control EVs. In CCl4-treated mice, YGJ-EV-derived miR-7045-5p ameliorated the liver fibrosis, improved the hepatic function, and suppressed the HSC activation by inhibiting the Akt/AMPK/TFEB pathway. In vitro, miR-7045-5p overexpression attenuated TGF-β1-induced HSC activation. Conclusion YGJ increases miR-7045-5p abundance in BMSC-EVs. YGJ-EVs alleviate liver fibrosis by delivering the anti-fibrotic miRNA miR-7045-5p, which inhibits the Akt/AMPK/TFEB pathway, thereby promoting lysosomal biogenesis and mitophagy in HSCs.

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Extracellular vesicles from Yiguanjian-primed bone-marrow mesenchymal stem cells ameliorate chronic liver fibrosis via miR-7045-5p

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Original ResearchVol. 16, Issue 669 • pp. 1-18DOI: 10.1186/s13287-025-04767-8

Targeting cellular senescence in progenitor cells as a strategy to enhance bone regeneration by cell therapies: a systematic review of pre-clinical investigations

Authors: Mayu Morita, Eshan B. Damle, Issei Shinohara, Masatoshi Murayama, Yosuke Susuki, Qi Gao, Chao Ma, Simon Kwoon-Ho Chow, Stuart Barry Goodman

Background With the global population aging, optimizing bone regeneration is becoming increasingly important for enhancing the quality of life among elderly individuals. Progenitor cell-based therapies, such as mesenchymal stromal cells and induced pluripotent stem cells for bone regeneration have shown challenges due to cellular senescence and the control of the differentiation processes remain significant hurdles. In particular, elevated expression of senescence markers may play a pivotal role in limiting bone regeneration. This systematic review examines how these senescence markers influence the efficacy of progenitor cell therapies and whether targeting them could improve outcomes. Methods We conducted a systematic literature review following the PRISMA guidelines, using the PubMed, Web of Science, Embase and Scopus with the algorithm of “bone regeneration AND senescence AND marker”. Data synthesis focused on human cell sources and specifically examined senescence markers related to bone regeneration. Results Studies using human cells were discussed in 101 papers. Based on our inclusion and exclusion criteria, 13 papers remained for our review on senescence markers in human cells within the context of bone regeneration and senescence, with and without interventional strategies. More than half of the cell sources in current aging-related studies are derived from bone marrow. Markers of aging relevant to bone regeneration include changes in cell size and morphology, increased levels of β-galactosidase (β-Gal) and Reactive Oxygen Species (ROS), and the presence of a senescence-associated secretory phenotype (SASP). Additionally, distinct senescence markers such as p16Ink4a, p21, and p53, and mitochondrial dysfunction were associated with reduced osteogenic potential and impaired regenerative capacity. Conclusion Bone marrow is the most common source of cells for studies of senescence. Cellular senescence characterized by elevated expression of specific markers was consistently shown to be negatively associated with osteogenic capacity and regenerative outcomes. The most common strategies to rejuvenate senescent cells include

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Targeting cellular senescence in progenitor cells as a strategy to enhance bone regeneration by cell therapies: a systematic review of pre-clinical investigations

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Original ResearchVol. 16, None • pp. 610DOI: 10.1186/s13287-025-04745-0

Engineering hypoimmune stem cell-derived beta cells

Authors: Benedikt J. M. Licht, Garry P. Duffy, Ruth E. Levey

In type 1 diabetes (T1D), autoimmune targeting destroys insulin-producing β cells in the pancreas, creating a chronic state of insulin deficiency. Islet transplantation presents a regenerative cell therapy approach that can re-establish insulin production and intrinsic glycemic control. However, islet transplantation is currently limited by a lack of cadaveric human islet donors and a requirement for life-long immune suppression following transplant. Developments in stem cell maturation and differentiation protocols have enabled production of insulin-producing cells ‘on demand’, thereby addressing the pancreatic donor tissue shortage. Continued reliance on immune suppression to avoid graft rejection, however, can result in opportunistic infection and malignancy, thus remaining a major obstacle for wide-spread application of insulin-producing β cell transplantation. As such, there has been significant interest in identifying alternative strategies for avoiding graft rejection without immune suppression including encapsulation and co-transplantation of accessory immunomodulating cells. However, these approaches are limited by incomplete immune isolation as well as concerns over maintenance of effector function and graft survival in vivo, respectively. Genetically engineering hypoimmune stem cell-derived β cells has thus emerged as a promising strategy for improving islet transplantation outcomes. These approaches leverage our understanding of pathways involved in immune regulation to selectively protect the transplanted insulin-producing cells without affecting systemic immune function. This review will summarize recent bioengineering approaches for generating hypoimmune stem cell-derived β cells. It will also discuss relevant safety concerns and potential genetic targets for future investigation that take inspiration from the development of immune evasive primary islets and chimeric antigen receptor (CAR) T cells.

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Engineering hypoimmune stem cell-derived beta cells

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Original ResearchVol. 16, None • pp. 625DOI: 10.1186/s13287-025-04732-5

Therapeatic evaluation and single cell analysis of adipose stromal vascular fraction isolation from a commercial cell separation system

Authors: Shunxin Han, Qian Zhang, Feng Lu, Junrong Cai

Background In the field of regenerative therapy, the stromal vascular fraction (SVF) extracted from adipose tissue has been widely recognized for its significant benefits. However, the cellular composition and therapeutic effect of SVF products prepared via different methods are unclear. Methods SVF cells were obtained via three approaches: (1) generation of the SVF via mechanical emulsification (M-SVF), (2) generation of the SVF via laboratory enzymatic digestion (L-SVF), and (3) generation of the SVF via commercial cell separation systems (C-SVF). We evaluated their healing effects on mouse wounds. Additionally, we utilized single-nucleus RNA sequencing (snRNA-seq) technology to explore the cellular composition of the C-SVF. Results The cell yield of C-SVF was comparable to that of L-SVF. During in vitro culture, C-SVF exhibited enhanced proliferation and a reduced proportion of apoptotic cells. In a mouse wound model, the application of C-SVF facilitated the closure of mouse wounds and improved collagen remodeling and angiogenesis in the wound area. Additional snRNA-seq analysis revealed that APOE+ adipose-derived stem cells and immune cells, especially M2 anti-inflammatory macrophages, are enriched in C-SVF, which together promote wound repair, and that APOE+ adipose-derived stem cells (ADSCs) and immune cells, especially M2 anti-inflammatory macrophages, are enriched in C-SVF, which jointly regulate and promote wound repair. Conclusion A commercial extraction system is an effective method for isolating viable SVF cells enriched with APOE+ ADSCs and M2 macrophages.

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$Therapeatic evaluation and single cell analysis of adipose stromal vascular fraction isolation from a commercial cell separation system$

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Original ResearchVol. 16, None • pp. 94DOI: 10.1186/s13287-025-04148-1

Long-term outcomes of mesenchymal stem cell therapy in severe COVID-19 patients: 3-year follow-up of a randomized, double-blind, placebo-controlled trial

Authors: Meng-Qi Yuan, Le Song, Ze-Rui Wang, Zi-Ying Zhang, Ming Shi, Junli He, Qiong Mo, Ning Zheng, Wei-Qi Yao, Yu Zhang, Tengyun Dong, Yuanyuan Li, Chao Zhang, Jinwen Song, Lei Huang, Zhe Xu, Xin Yuan, Jun-Liang Fu, Cheng Zhen, Jianming Cai, Jinghui Dong, Jianzeng Zhang, Wei-Fen Xie, Yonggang Li, Bo Zhang, Lei Shi, Fu-Sheng Wang

Background The long-term effects and outcomes of human mesenchymal stem cell (MSC) therapy in patients with severe coronavirus disease 2019 (COVID-19) remain poorly understood. This study aimed to evaluate the extended safety and efficacy of MSC treatment in severe patients with COVID-19 who participated in our earlier randomized, double-blind, placebo-controlled clinical trial, with follow-up conducted over 3 years. Methods One hundred patients with severe COVID-19 were randomized to receive either an MSC infusion (n=65, 4×10^7 cells/dose, on days 0, 3, and 6) or a placebo, with both groups receiving the standard of care. At 36 months post-MSC therapy, patients were followed up to long-term safety and efficacy, particularly the effects of MSC therapy on persistent COVID-19 symptoms. Evaluated outcomes included lung imaging results, 6-min walking distance (6-MWD), pulmonary function test results, quality of life scores based on the Short Form-36 (SF-36) health survey, Long COVID symptoms, new-onset comorbidities, tumor marker levels, and rates of COVID-19 reinfection. Results Three years post-treatment, 46.94% (23/49) of patients in the MSC group and 34.48% (10/29) in the placebo group showed normal findings on computed tomography (CT) images (odds ratio [OR]=1.68, 95% confidence interval [CI]: 0.65–4.34). The general health (GH) score from the SF-36 was higher in the MSC group (67.0) compared to the placebo group (50.0), with a difference of 12.86 (95% CI: 1.44–24.28). Both groups showed similar results for total lung severity scores (TSS), 6-MWD, pulmonary function tests, and Long COVID symptoms. No significant differences between groups were observed in new-onset complications (including tumorigenesis) or tumor marker levels. After adjusting for China’s dynamic zero-COVID-19 strategy, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfection rates were 53.06% (26/49) in the MSC group and 67.86% (19/28) in the placebo group (OR=0.54, 95% CI: 0.20–1.41). Conclusions These findings support the long-term safety of MSC therapy in patients with severe COVID-19 over 3 years. MSC treatment may offer potential benefits for lung recovery and improved quality of life in patients experiencing Long COVID symptoms. Trial registration: ClinicalTrials.gov, NCT04288102. Registered 28 February 2020, https://clinicaltrials.gov/study/NCT04288102.

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Long-term outcomes of mesenchymal stem cell therapy in severe COVID-19 patients: 3-year follow-up of a randomized, double-blind, placebo-controlled trial

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Original ResearchVol. 16, None • pp. 606DOI: 10.1186/s13287-025-04621-x

Effects of miR-210-3p/SDF2 and miR-31-5p/FGF7 from hypoxic endometrial exosomes on UCB-MSC proliferation, migration, and differentiation

Authors: Simiao Liu, Wanyu Zhang, Chengyan Deng, Hanbi Wang

Background Mesenchymal stem cells (MSCs) isolated from umbilical cord blood (UCB) exhibit significant therapeutic efficacy in endometriosis; however, the molecular mechanisms governing their regulation remain incompletely elucidated. This study delves into the regulatory functions of miR-210-3p and miR-31-5p, which are secreted via exosomes from hypoxia-damaged endometrial epithelial cells, in modulating the behavior of UCB-MSCs. Methods UCB-MSCs were transfected with specific inhibitors targeting miR-210-3p and miR-31-5p. Proliferation and migratory capacities were quantified using CCK8, EdU incorporation, Transwell, and scratch wound healing assays. Western blotting was employed to assess the expression of endometrial epithelial markers (CD9 and CK19) and stromal markers (Vimentin and CD13), alongside the phosphorylation status of JAK2 and STAT3. Dual-luciferase reporter assays were conducted to validate SDF2 and FGF7 as direct targets of miR-210-3p and miR-31-5p, respectively. Results Suppression of miR-210-3p and miR-31-5p significantly augmented the proliferative and migratory abilities of UCB-MSCs, while simultaneously enhancing their differentiation into endometrial epithelial cells and attenuating their transition into stromal cells. Concurrently, the phosphorylation levels of JAK2 and STAT3 were markedly elevated. Overexpression of SDF2 and FGF7 further amplified the proliferative, migratory, and epithelial differentiation capacities of UCB-MSCs, accompanied by heightened activation of the JAK2/STAT3 signaling pathway. Notably, SDF2 overexpression and FGF7 overexpression effectively counteracted the inhibitory effects exerted by miR-210-3p and miR-31-5p mimics on UCB-MSC proliferation, migration, and epithelial differentiation, mediated through the modulation of JAK2/STAT3 signaling. Conclusion miR-210-3p and miR-31-5p orchestrate the functional dynamics of UCB-MSCs by targeting SDF2 and FGF7, respectively, through the JAK2/STAT3 pathway. These findings unveil novel mechanistic insights into the regenerative potential of UCB-MSCs, offering promising avenues for therapeutic advancements in endometriosis.

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Effects of miR-210-3p/SDF2 and miR-31-5p/FGF7 from hypoxic endometrial exosomes on UCB-MSC proliferation, migration, and differentiation

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Original ResearchVol. 16, None • pp. 214DOI: 10.1186/s13287-025-04350-1

Phase separation participates in the genetic regulation mechanism of hematopoietic stem cells: potential therapeutic methods

Authors: XinYu Tang, Yan Wang, RuiRong Xu

Hematopoietic stem cells (HSCs) are the primitive cells that give rise to common precursors for all blood cell lineages. Abnormalities in their number and/or function are important factors leading to the decline of immune function and the occurrence of various systemic diseases. Phase separation refers to a physicochemical mechanism in which intracellular liquid-liquid phase separation (LLPS) forms membrane-less organelles. It participates in various physiological activities and is related to the occurrence of diseases. Studies have shown that the functional activity of HSCs is regulated by complex mechanisms, and phase separation is closely related to these complex mechanisms such as genetic regulation, epigenetic regulation, microenvironment regulation, gene expression, autophagy degradation, and cell proliferation. With the deepening of research, the importance of phase separation in the pathogenesis and treatment of diseases such as leukemia and tumors has gradually emerged, but the deep mechanism of its regulation of HSCs genetic regulation still lacks exploration, and the direction of clinical targeted therapy is not yet clear. Here, we will summarize and elaborate the genetic regulation mechanism of HSCs, discuss the relationship between phase separation and the functional regulation of HSCs, and analyze the possibility of phase separation participating in the genetic regulation of HSCs to treat diseases, in order to provide help for the clinical implementation of targeted therapy for HSCs regulation.

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Phase separation participates in the genetic regulation mechanism of hematopoietic stem cells: potential therapeutic methods

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Original ResearchVol. 16, None • pp. 174DOI: 10.1186/s13287-025-04282-w

Erythropoietin delivery through kidney organoids engineered with an episomal DNA vector

Authors: Z. Du, A. Bas-Cristóbal Menéndez, M. Urban, A. Hartley, D. Ratsma, M. Koedam, T. P.P. van den Bosch, M. Clahsen-van Groningen, J. Gribnau, J. Mulder, M. E.J. Reinders, C. C. Baan, B. van der Eerden, R. P. Harbottle, Martin J. Hoogduijn

Background The kidney’s endocrine function is essential for maintaining body homeostasis. Erythropoietin (EPO) is one of the key endocrine factors produced by the kidney, and kidney disease patients frequently experience anemia due to impaired EPO production. In the present study we explored the potential of human induced pluripotent stem cell (iPSC)-derived kidney organoids to restore EPO production. Methods EPO secretion by kidney organoids was examined under 1% and 20% oxygen levels. To increase the EPO secreting capacity of kidney organoids, iPSC were genetically engineered with a non-integrating scaffold/matrix attachment region (S/MAR) DNA vector containing the EPO gene and generated EPO-overexpressing (EPO+) kidney organoids. To assess the physiological effects of EPO+ organoids, 2–8 organoids were implanted subcutaneously in immunodeficient mice. Results Kidney organoids produced low amounts of EPO under 1% oxygen. EPO S/MAR DNA vectors persisted and continued to robustly express EPO during iPSC expansion and kidney organoid differentiation without interfering with cellular proliferation. EPO+iPSC demonstrated efficient differentiation into kidney organoids. One-month post-implantation, EPO+ organoids displayed continuously elevated EPO mRNA levels and significantly increased endothelial cell numbers compared to control organoids. Hematocrit levels were notably elevated in mice implanted with EPO+ organoids in an organoid number-dependent manner. EPO+ organoids furthermore influenced bone homeostasis in their hosts, evidenced by a change in trabecular bone composition. Conclusion Kidney organoids modified by EPO S/MAR DNA vector allow stable long-term delivery of EPO. The observed physiological effects following the implantation of EPO+ organoids underscore the potential of gene-edited kidney organoids for endocrine restoration therapy.

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Erythropoietin delivery through kidney organoids engineered with an episomal DNA vector

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Original ResearchVol. 16, None • pp. 460DOI: 10.1186/s13287-025-04613-x

β-Sitosterol preconditioning enhances the resistance of BMSCs and chondrocyte to oxidative stress and promotes cartilage repair in osteoarthritis

Authors: Chengyin Liu, Xiaoman Wang, Yanyan Zhang, Hongfan Ge, Qi Chang, Zhenlei Zhou

Background Osteoarthritis (OA) is a joint disorder that severely affects patients’ mobility, overall health, and ability to perform daily activities. Despite advancements in therapeutic strategies, stem cell-based therapies for OA still face challenges, particularly in enhancing the antioxidative capacity of stem cells to improve therapeutic outcomes. Therefore, this study aimed to explore the potential of β-sitosterol in this context. Methods This study evaluated the protective effects of β-sitosterol on bone marrow-derived mesenchymal stem cells (BMSCs) and chondrocytes under oxidative stress conditions and assessed its potential in promoting cartilage repair in a rabbit OA model. Cell viability, gene expression, oxidative stress markers, and mitochondrial function were examined. In vivo therapeutic effects were evaluated through histological and immunohistochemical analyses. Results The results revealed that β-sitosterol significantly enhanced BMSC viability, upregulated the expression of Col2a1 and aggrecan, while inhibiting MMP13 expression. Furthermore, β-sitosterol effectively alleviated oxidative stress and preserved mitochondrial function in BMSCs. Notably, BMSCs pretreated with β-Sitosterol exhibited a higher potential for facilitating cartilage regeneration in the OA model, as evidence by histopathological analysis. Conclusions These findings suggest that β-sitosterol possesses significant antioxidative and chondroprotective properties, which enhance the therapeutic efficacy of BMSCs in addressing OA-related cartilage damage.

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β-Sitosterol preconditioning enhances the resistance of BMSCs and chondrocyte to oxidative stress and promotes cartilage repair in osteoarthritis

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Original ResearchVol. 16, None • pp. 119DOI: 10.1186/s13287-025-04258-w

The local pulsatile parathyroid hormone delivery system induces the osteogenic differentiation of dental pulp mesenchymal stem cells to reconstruct mandibular defects

Authors: Yuanyuan Jia, Mianmian Duan, Yan Yang, Duchenhui Li, Dongxiang Wang, Zhenglong Tang

Background Tumors and injuries often lead to large mandibular defects. Accelerating the osteogenesis of large bone defect areas is a major concern in current research. In this study, dental pulp mesenchymal stem cells (DPSCs) were used as seed cells, and the local pulsatile parathyroid hormone (PTH) delivery system was used as an osteogenic-inducing active ingredient to act on DPSCs and osteoblasts, which were applied to the jaw defect area to evaluate its therapeutic effect on bone regeneration. Methods Pulsatile delivery systems, both with and without PTH, were developed following the protocols outlined in our previous study. In vitro, the biocompatibility of the pulsatile delivery system with DPSCs was assessed using the Cell Counting Kit-8 (CCK8) assay and live/dead cell staining. Osteogenic differentiation was evaluated through alkaline phosphatase staining and alizarin red staining. In vivo, critical bone defects with a diameter of 10 mm were created in the mandibles of white rabbits. The osteogenic effect was further assessed through gross observation, X-ray imaging, and histological examination. Results In vitro experiments using CCK8 assays and live/dead cell staining demonstrated that DPSCs successfully adhered to the surface of the PTH pulsatile delivery system, showing no significant difference compared to the control group. Furthermore, alkaline phosphatase staining and Alizarin Red staining confirmed that the localized pulsatile parathyroid hormone delivery system effectively induced the differentiation of DPSCs into osteoblasts, leading to the secretion of abundant calcium nodules. Animal studies further revealed that the PTH pulsatile delivery system promoted the osteogenic differentiation of DPSCs, facilitating the repair of critical mandibular bone defects.

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The local pulsatile parathyroid hormone delivery system induces the osteogenic differentiation of dental pulp mesenchymal stem cells to reconstruct mandibular defects

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Original ResearchVol. 16, None • pp. 580DOI: 10.1186/s13287-025-04681-z

Spatial self-organization of cancer stem cell niches revealed by live single-cell imaging

Authors: Mathilde Brulé, Anais Horochowska, Emeline Fontaine, Raoul Torero-Ibad, Flavie Woesteland, Marie Denoulet, Jean Pesez, Eric Adriaenssens, Robert-Alain Toillon, Xuefen Le Bourhis, Benjamin Pfeuty, Chann Lagadec, François Anquez

Background: Phenotypic plasticity is a major factor in tumor heterogeneity and treatment resistance. In particular, cancer stem cells (CSCs) represent a small subpopulation within tumors that possesses self-renewal and tumor-forming capabilities. Understanding reprogramming, maintenance, and lineage properties of CSCs requires dedicated tools to disentangle the respective influences of phenotypic inheritance and cell-cell interactions. Methods: Here, we set up ultra-wide field microscopy to image breast cancer cell lines expressing a stemness fluorescent reporter over several days. The fluorescent reporter distinguishes three phenotypes: CSCs, cancer differentiated cells (CDCs), and intermediate/transiting cancer cells (iCCs). Results: Spatial statistics indicate significant zonation in which CSCs cluster together and are spatially separated from CDCs, forming patterns resembling niches. Surprisingly, single-cell time series reveal spontaneous reprogramming events from CDC to CSC even in unperturbed populations. We identify that such transitions are prone to arise during the cell cycle. Moreover, lineage analysis shows that the phenotype is partially inherited from ancestor cells. However, such heredity is not sufficient to explain the spatial properties of the cell population, which also depend on cell-cell interactions. Indeed, we find that phenotypic transitions of cancer cells are influenced by the phenotypic state of neighboring cells. Reprogramming into CSCs is respectively promoted and inhibited by the presence of CSCs and CDCs in the neighborhood. Conclusions: Altogether, our results disentangle how phenotypic inheritance and intercellular interactions orchestrate the spatio-temporal self-organization of cancer cell heterogeneity, maintaining a subpopulation of CSCs within niches.

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Spatial self-organization of cancer stem cell niches revealed by live single-cell imaging

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Original ResearchVol. 16, None • pp. 249DOI: 10.1186/s13287-025-04377-4

A meta-analysis on application and prospect of cell therapy in the treatment of diabetes mellitus

Authors: Hanluo Li, Cheng Chen, Yuansheng Wang, Wei Yi, Peipei Guo, Chenguang Yao, Jinbiao Liu, Yanhong Wei, Kanghong Hu, Xiaoke Shang, Sini Kang

Objective Diabetes mellitus (DM) is a grave autoimmune disorder because of no insulin self-generation. Currently, mainly clinical methods exist, serious adverse effects leading to stem cell therapy are considered. The mesenchymal stem cells (MSCs), require high differentiation capacity and are judged as crucial in DM treatment. The meta-analysis aimed to systemically analyze the particular types of MSCs which play a more important role in DM and which DM is treated more effectively. Method A systematic review was conducted on the published literature, clinical trials and observational studies, utilizing databases such as PubMed, Embase, Cochrane and clinicaltrial.gov. RevMan software was adopted to draw Forest Plot and Funnel Plot, and subgroup analysis were employed to evaluate heterogeneity between different groups. Results We identified the meta-analyses of 34 unique random controlled trials and divided our own systematic reviews into 8 groups. The MSCs were associated with placebo (OR=2.79, 95% CI [1.63, 4.75]), Standard Clinical Treatment (SCT) (OR=4.12, 95% CI [2.76, 6.14]), and monocyte (OR=6.52, 95% CI [3.56, 9.48]). The comparison between Autologous MSCs and Allogenic MSCs (OR=4.64, 95% CI [3.42, 6.31]), Autologous BMMSCs and other MSCs (OR=5.28, 95% CI [3.64, 7.66]), Allogenic ASCs and UCMSCs (OR=3.54, 95% CI [1.83, 6.86]), Type I DM and Type II DM (OR=3.10, 95% CI [1.79, 5.38]), intravenous injection and other injections (OR=4.81, 95% CI [3.34, 6.94]), diabetic foot ulcers and diabetic neurological disease (OR=3.88,,95% CI [2.53,5.95]). Conclusion Current evidence suggests that MSCs hold significant potential for treating DM, demonstrating considerably high safety and efficacy. MSCs exhibit higher therapeutic benefits compared to monocytes, with autologous MSCs offering better clinical outcomes than allogenic sources. MSCs (BMMSCs) proved more effective than other types of MSCs. However, no significant differences were observed between adipose-derived MSCs (ASCs)

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A meta-analysis on application and prospect of cell therapy in the treatment of diabetes mellitus

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Original ResearchVol. 16, Issue 1 • pp. 115DOI: 10.1186/s13287-025-04213-9

Purine metabolism in bone marrow microenvironment inhibits hematopoietic stem cell differentiation under microgravity

Authors: Xiru Liu, Hao Zhang, Jinxiao Yan, Penghui Ye, Yanran Wang, Nu Zhang, Zhenhao Tian, Bin Liu, Hui Yang

Background Spaceflight and microgravity environments have been shown to cause significant health impairments, including bone loss, immune dysfunction, and hematopoietic disorders. Hematopoietic stem cells (HSCs), as progenitors of the hematopoietic system, are critical for the continuous renewal and regulation of immune cells. Therefore, elucidating the regulatory mechanisms governing HSC fate and differentiation in microgravity environments is of paramount importance. Methods In this study, hindlimb unloading (HU) was employed in mice to simulate microgravity conditions. After 28 days of HU, cells were isolated for analysis. Flow cytometry and colony-forming assays were utilized to assess changes in HSC proliferation and differentiation. Additionally, transcriptomic and untargeted metabolomic sequencing were performed to elucidate alterations in the metabolic pathways of the bone marrow microenvironment and their molecular regulatory effects on HSCs fate. Results Our findings revealed that 28 days of HU impaired hematopoietic function, leading to multi-organ damage and hematological disorders. The simulated microgravity environment significantly increased the HSCs population in the bone marrow, particularly within the long-term and short-term subtypes, while severely compromising the differentiation capacity of hematopoietic stem/progenitor cells. Transcriptomic analysis of HSCs, combined with metabolomic profiling of bone marrow supernatants, identified 1,631 differentially expressed genes and 58 metabolites with altered abundance. Gene set enrichment analysis indicated that HU suppressed key pathways, including hematopoietic cell lineage and MAPK signaling. Furthermore, integrated analyses revealed that metabolites affected by HU, particularly hypoxanthine enriched in the purine metabolism pathway, were closely associated with hematopoietic cell lineage and MAPK signaling pathways. Molecular docking simulations and in vitro experiments confirmed that hypoxanthine interacts directly with core molecules within these pathways, influencing their expression. Conclusions These findings demonstrate that hypoxanthine in the bone marrow supernatant acts as a signaling mediator under microgravity, influencing HSCs fate by modulating hematopoietic cell lineage and MAPK signaling pathways. This study offers novel insights into the impact of microgravity on HSC fate and gene expression, underscoring the pivotal role of bone marrow microenvironmental metabolic changes in regulating key signaling pathways that determine hematopoietic destiny.

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Purine metabolism in bone marrow microenvironment inhibits hematopoietic stem cell differentiation under microgravity

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Original ResearchVol. 16, None • pp. 444DOI: 10.1186/s13287-025-04549-2

Multi-function of adipose-derived stem cells on gut disorder: from bench to bedside

Authors: Jiatong Zhao, Shuzi Xin, Xiaohui Liu, Weikai Shi, Boya Wang, Hongli Wang, Yi Wang, Rongxuan Hua, Yize Li, Lei Gao, Xin Lu, Jingdong Xu

Adipose-derived stem cells (ADSCs) are a specific type of mesenchymal stem cells (MSCs) obtained easily from adipose tissue (AT). Compared with MSCs, ADSCs are easier to obtain, have fewer ethical issues, and have a higher proliferative capacity, which makes them a promising type of stem cell in regenerative medicine. ADSCs possess impressive capabilities in cell regeneration as well as differentiation, making them promising candidates for injury repair, tissue regeneration and alleviation of inflamed tissues. At present, most clinical studies on ADSCs focus on the treatment of wounds, multiple sclerosis, soft tissue trauma, aging, diabetes, Parkinson’s disease, bone and cartilage regeneration, stroke, and spinal cord injury, while its clinical applications in the gastrointestinal tract are relatively few. Therefore, this review summarizes the findings of preclinical experiments, clinical trials, and areas that may require further development of ADSCs in the treatment of digestive disorders, including inflammatory bowel disease (IBD), colorectal cancer (CRC), colorectal fibrosis, hepatocellular carcinoma, hepatic fibrosis, gastric cancer (GC), gastrostomy closure and radiation-induced proctitis. The review is concluded by discussing the goals for improvement and future directions for ADSCs before large-scale clinical application.

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Multi-function of adipose-derived stem cells on gut disorder: from bench to bedside

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Original ResearchVol. 16, Issue 1 • pp. 63DOI: 10.1186/s13287-025-04179-8

Induction of the p21/CDK6 pathway and alteration of the immune microenvironment by the stem cell marker CBX3 in melanoma

Authors: Wanxian Chen, Linsa Zhou, Jingjing Jiang, Jiasheng Chen, Deyi Geng, Yaokun Chen, Xiaosha Han, Qihu Xie, Genghong Guo, Xuefen Chen, Shijie Tang, Xiaoping Zhong

Background As one of the stem cell markers, chromobox protein homolog 3 (CBX3) participates in multiple signaling pathways that affect the progression of various tumors. However, the role of CBX3 in melanoma remains unclear, and the mechanisms by which CBX3 may regulate immunotherapy outcome remain largely unknown. Methods We used the Cancer Genome Atlas, Genotype-Tissue Expression portal, and Gene Expression Omnibus database to estimate CBX3 expression and its prognostic effect in melanoma. The role of CBX3 in proliferation and migration of melanoma cells were examined using the CCK8, cloning, wound healing, and transwell assays. The effect of CBX3 on melanoma tumorigenesis was assessed using an in vivo animal model. The role of CBX3 in cell cycle was examined using flow cytometry, and expression levels of cell cycle-related genes and proteins in cells with altered CBX3 levels were analyzed using qPCR and western blotting. The function of CBX3 in the immune microenvironment of melanoma was studied using single-cell RNA sequencing and public databases. Results We found that CBX3 was highly expressed in melanoma with poor prognosis. CBX3 promoted the proliferation and migration of melanoma cells in vivo and in vitro. Functional analysis revealed that CBX3 regulates cell cycle, as it accelerated the G1 to S transition, decreased p21 expression, and increased CDK6 expression. Finally, single-cell sequencing and immune-related assays showed that CBX3 is immunogenic and can change the immune microenvironment of melanoma. Conclusions We conclude that the stem cell marker, CBX3 activates the p21/CDK6 pathway and alters the immune microenvironment in melanoma.

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Induction of the p21/CDK6 pathway and alteration of the immune microenvironment by the stem cell marker CBX3 in melanoma

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Original ResearchVol. 16, None • pp. 389DOI: 10.1186/s13287-025-04501-4

Highly efficient XIST reactivation in female hPSC by transient dual inhibition of TP53 and DNA methylation during Cas9 mediated genome editing

Authors: Nami Motosugi, Keita Hasegawa, Natsumi Kurosaki, Erika Kawaguchi, Kenji Izumi, Yumi iida, Misaki Higashiseto, Keiko Yokoyama, Ayumi Sasaki, Kazuhiko Nakabayashi, Atsushi Fukuda

The irreversible erosion of X-chromosome inactivation (XCI) due to repression of the long non-coding RNA XIST presents a major challenge for disease modeling and raises safety concerns for the clinical application of female human pluripotent stem cells (hPSCs) due to the aberrant overexpression of X-linked genes. While Cas9-mediated non-homologous end joining (NHEJ) targeting the XIST promoter can induce DNA demethylation and restore XCI by reactivating XIST, its efficiency remains low. Here, we introduce a highly efficient strategy for XIST reactivation by combining TP53 inhibition with suppression of DNA methylation maintenance during Cas9-mediated NHEJ. This dual-inhibition approach increased the proportion of XIST-positive hPSCs from ~5 to ~43.7%, providing a robust method for stabilizing XCI in female hPSCs for diverse applications.

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Highly efficient XIST reactivation in female hPSC by transient dual inhibition of TP53 and DNA methylation during Cas9 mediated genome editing

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Original ResearchVol. 16, None • pp. 321DOI: 10.1186/s13287-025-04426-y

Blastocyst complementation: current progress and future directions in xenogeneic organogenesis

Authors: Paula Barlabé, Xabier L. Aranguren, Giulia Coppiello

The generation of organs derived from pluripotent stem cells can be achieved in vivo through the blastocyst complementation technique. This method is based on the introduction of pluripotent stem cells into organogenesis-disabled pre-implantation embryos, where environmental signals instruct donor cells to colonize the vacant niche and to develop into the missing organ. When applied interspecies, this approach has the potential to produce human organs in genetically engineered livestock, offering a promising solution to the global transplants’ shortage crisis. In this review, we summarize the current progress in blastocyst complementation research and highlight the key challenges that must be addressed to advance this field.

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Blastocyst complementation: current progress and future directions in xenogeneic organogenesis

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Original ResearchVol. 16, Issue 277 • pp. 1-15DOI: 10.1186/s13287-025-04398-z

CD73-expressing endometrial regenerative cell-derived exosomes mitigate acute cardiac allograft rejection through regulating adenosine metabolism in mice

Authors: Chenglu Sun, Dejun Kong, Hong Qin, Shilong Li, Conglin Wang, Shaohua Ren, Yini Xu, Hongda Wang, Hao Wang

Background Organ transplantation is a life-saving option for end-stage organ dysfunction, but long-term graft survival is limited by unavoidable allograft rejection. While endometrial regenerative cells (ERCs) have been shown to alleviate acute rejection, the underlying mechanisms are not fully understood. This study explored whether ERC-derived exosomes contribute to this effect through CD73-mediated immunoregulation. Methods ERCs were pretreated with GW4869, an exosome inhibitor, to block exosome secretion, and CRISPR-Cas9-based CD73 knockout was performed to validate the role of CD73 in the ERC and ERC-exos. CD73 enzyme activity was measured using an AMP assay in vitro, whereas ATP, AMP, and adenosine levels were quantified using mass spectrometry in vivo. A murine allogeneic heart transplantation model (BALB/c to C57BL/6) was established to evaluate the immunoregulatory effects of ERC-exos in vivo. Graft tissues were analyzed by H&E staining, and immunohistochemistry and flow cytometry analysis of the spleens were performed to assess graft rejection. In vitro, flow cytometry was used to examine CD4+ T-cell activation, proliferation, differentiation, and subsets. Adenosine receptor inhibitors were used to identify receptor-mediated CD73-exosome signaling, and the potential of combining CD73-expressing exosomes with rapamycin to promote long-term graft survival was explored. Results GW4869 reduces the ability of ERCs to inhibit CD4+ T-cell activation and proliferation in vitro and attenuates the ERC-mediated suppression of acute allograft rejection in vivo. ATP, AMP and ADO increase adenosine 2a receptor (A2aR) but not A2bR expression on CD4+ T cells. CD73-expressing ERC-derived exosomes (ERC-exos) metabolize AMP into adenosine, leading to the inhibition of CD4+ T-cell activation, proliferation, and Th1 differentiation in vitro. This regulatory effect is reversed by the A2a receptor inhibitor CPI444. Furthermore, CD73 depletion blocks ERC-derived exosome-mediated adenosine production and impairs the ability of these cells to inhibit CD4+ T-cell activation and proliferation in vitro, as well as attenuate acute cardiac allograft rejection in vivo. Finally, the combination of ERC-exos with rapamycin significantly prolonged allograft survival from 15 days with rapamycin monotherapy to 38 days. Conclusion CD73 expression is crucial for the ability of ERC-exos to generate adenosine to mitigate acute cardiac allograft rejection in mice. ERC-exos combined with rapamycin can prolong allograft survival.

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CD73-expressing endometrial regenerative cell-derived exosomes mitigate acute cardiac allograft rejection through regulating adenosine metabolism in mice

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Original ResearchVol. 16, Issue 611 • pp. 1-11DOI: 10.1186/s13287-025-04703-w

A phase I, open-label study of intravenous human dental pulp stem cells (NestaCell®) at two dose levels in patients with Huntington’s disease

Authors: Joyce Macedo Sanches Fernandes, Eduardo Pagani, Cristiane Valverde Wenceslau, Leandro Hideki Ynoue, Luciana Ferrara, Irina Kerkis

Background Huntington’s disease (HD) is a progressive neurodegenerative disorder with no approved disease-modifying therapies. Human dental pulp stem cells (hDPSCs) offer potential therapeutic benefits due to their neurogenic, neurotrophic, and immunomodulatory properties. This prospective, open-label, single-centre, first-in-human clinical trial evaluated the safety, tolerability, and preliminary efficacy of intravenous hDPSC in patients with HD. Methods Six male patients with HD received intravenous infusions of hDPSCs in two dosage cohorts: three patients received 1 million cells/kg, and three received 2 million cells/kg. The treatment protocol consisted of cycles of three infusions at monthly intervals followed by subsequent administration cycles every six months, as per a protocol amendment based on the initial favourable safety outcomes. The total number of infusions ranged from 4 to 26 over the five years. During the first year, all patients underwent intensive multiparametric monitoring in an intensive care unit (ICU) for 48 h after each infusion. Results No adverse events occurred during the 48-h ICU monitoring or within 15 days post-infusion. Of 41 treatment-emergent adverse events (TEAEs) reported during follow-up, 35 were judged unrelated to the hDPSCs, mainly reflecting disease progression or incidental findings. Six treatment-emergent adverse events (TEAEs) were considered treatment-related, involving transient changes in hair pigmentation or regrowth. One patient discontinued due to a serious adverse event—lung cancer arising from a pre-existing pulmonary nodule identified at enrolment. Genetic analysis of the excised tumour showed no evidence of investigational product engraftment, supporting its non-tumorigenic nature. The same patient experienced a severe depressive episode

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A phase I, open-label study of intravenous human dental pulp stem cells (NestaCell®) at two dose levels in patients with Huntington’s disease

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Original ResearchVol. 16, None • pp. 584DOI: 10.1186/s13287-025-04706-7

Mesenchymal stem cells inhibit mitochondrial fission by upregulating armadillo repeat containing 1, ameliorating oxidative stress in renal fibrosis

Authors: Tao Li, Chuan Guo, Qin Liu, Fengting Jing, Min Zhao, Hemin Xiong, Chang Li, Wei Zhang, Bo Chen

Background Oxidative stress damage is the important mechanism that promotes the process of fibrosis. Whether mesenchymal stem cells (MSCs) regulate mitochondrial dynamics and oxidative stress via armadillo repeat containing 1 (ARMC1) in renal fibrosis? Methods Using proteomics analysis, compare the significant differences in renal tissue proteins before and after MSCs intervention in adenine-induced nephropathy. Using a lentiviral vector to overexpress the ARMC1 gene in HK-2 cells, with the empty vector as a control. MSCs conditioned media (MSCs-CM) was applied to TGF-β1 treated cells, and MSCs were used in a cisplatin-induced nephropathy mouse model to assess mitochondrial dynamics, ROS generation, antioxidant stress, and fibrosis indicators, with Mdivi-1 (a Drp1 inhibitor) and Apocynin (a selective NADPH oxidase inhibitor) as positive controls. Results Renal proteomics showed that MSCs increased ARMC1 protein in the renal tissue of adenine nephropathy (3.521 times). In vitro, MSCs-CM increased ARMC1, reduced DRP1, and enhanced OPA1 and MFN2, lowering ROS, boosting mitochondrial bioactivity, and increasing antioxidant proteins NRF2, SOD1, SOD2, and CAT while decreasing fibrosis markers α-SMA, FN, COL-I, and KIM-1, and raising E-cadherin. The indicator variations in ARMC1-OE cells and OE-Con cells were similar between subgroups; Notably, under identical treatment conditions, the shifts in indicators within ARMC1-OE cells were more significant than those observed in OE-Con cells. In cisplatin-induced nephropathy mice, MSCs, Apocynin, and Mdivi-1 improved renal function and reduced interstitial collagen deposition, inhibited mitochondrial fission, enhanced antioxidant capacity, and reduced fibrosis. However, individual interventions were found to be less effective than their combined counterparts, with the synergistic impact of MSCs and Mdivi-1 achieving the most remarkable outcomes. Conclusion MSCs have the potential to improve renal fibrosis by influencing mitochondrial dynamics and oxidative stress through the upregulation of ARMC1 expression. ARMC1 may be an effective target for anti-fibrosis.

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Mesenchymal stem cells inhibit mitochondrial fission by upregulating armadillo repeat containing 1, ameliorating oxidative stress in renal fibrosis

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Original ResearchVol. 16, None • pp. 335DOI: 10.1186/s13287-025-04474-4

Engineering biomimetic bone marrow niche with gene modified mesenchymal stromal cells for ex vivo culture of human hematopoietic stem and progenitor cells

Authors: Sevanthy Suresh, Vigneshwaran Venkatesan, Manoj Kumar K. Azhagiri, Gokulnath Mahalingam, Prathibha Babu Chandraprabha, Mohankumar K. Murugesan, Sanjay Kumar, Saravanabhavan Thangavel, Srujan Marepally

Background: Hematopoietic Stem and Progenitor Cells (HSPCs) gene therapy has shown significant progress, with commercial approval for at least four distinct haematological disorders, and poised for a rapid expansion in the upcoming years. Despite these advancements, the ex vivo culture of HSPCs continues to present significant challenges. The stress induced by ex vivo culture can negatively impact transplantation outcomes, while the need for exogenous cytokine supplementation contributes to the high costs associated with gene therapy products. Methods: We developed genetically modified human bone marrow MSCs (GM-MSCs) secreting cytokines such as Stem cell factor (SCF), Thrombopoietin (TPO), FMS-like tyrosine kinase-3-ligand (FLT3L), and Interleukin-3 (IL3), closely resembling bone marrow cellular niche to augment HSPCs culture. Results: HSPCs proliferate on GM-MSCs akin to standard conditions, devoid of external cytokine supplementation and these HSPCs retain their stem cell characteristics, colony-forming potential, stemness gene signatures, and capacity for long-term multilineage reconstitution in NBSGW mice. We demonstrate that our biomimetic feeder layer supports and alleviates stress associated with Homology Directed Repair (HDR) mediated gene-editing of HSPCs for fetal haemoglobin reactivation for a potential application in β-hemoglobinopathies gene therapy. Conclusion: Our GM-MSCs offer a compelling alternative to traditional cytokine supplementation by establishing a biomimetic bone marrow niche that fosters HSPC expansion while maintaining their stemness. These findings underscore the potential of engineered MSCs to revolutionize ex vivo HSPCs culture, ultimately enhancing their therapeutic value for gene therapy applications.

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Engineering biomimetic bone marrow niche with gene modified mesenchymal stromal cells for ex vivo culture of human hematopoietic stem and progenitor cells

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Original ResearchVol. 16, None • pp. 96DOI: 10.1186/s13287-025-04173-0

Melatonin-pretreated mesenchymal stem cell-derived exosomes alleviate cavernous fibrosis in a rat model of nerve injury-induced erectile dysfunction via miR-145-5p/TGF-β/Smad axis

Authors: Xiaolin Zhang, Mengbo Yang, Xinda Chen, Ming Zhang, Yiliang Peng, Mujun Lu

Background Cavernous nerve injury-induced erectile dysfunction (CNI-ED) is a common complication after radical prostatectomy. Conventional treatment approaches have had little success in treating the severe cavernous fibrosis which is a consequence of CNI-ED. Methods Pre-treatment of adipose-derived stem cells with melatonin allows for the extraction of active exosomes (MT-hASC-EVs) from the conditioned medium. The therapeutic effects of MT-hASC-EVs were assessed in a rat model of CNI-ED, and the anti-fibrotic properties were evaluated. MicroRNA sequencing was used to identify specific microRNAs highly expressed in MT-hASC-EVs, and differential microRNAs were screened for regulatory pathways through target gene enrichment analysis. Finally, the conclusions from bioinformatics analysis were validated through in vitro experiments. Results Intracavernous injection of MT-hASC-EVs significantly restored erectile function and reduced the extent of corpus cavernosum fibrosis in the CNI-ED rat model. MT-hASC-EVs promoted the proliferation and anti-apoptotic effects of corpus cavernosum smooth muscle cells (CCSMCs) in vitro. Mechanistically, MT-hASC-EVs inhibit fibrosis by delivering miR-145-5p, which targets TGF-β2/Smad3 axis. Conclusions MT-hASCs-EVs can inhibit cavernous fibrosis and improve erectile function in a rat model of CNI-ED by targeting the miR-145-5p/TGF-β/Smad axis.

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Melatonin-pretreated mesenchymal stem cell-derived exosomes alleviate cavernous fibrosis in a rat model of nerve injury-induced erectile dysfunction via miR-145-5p/TGF-β/Smad axis

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Original ResearchVol. 16, None • pp. 316DOI: 10.1186/s13287-025-04463-7

The influence of femtosecond laser intrastromal lenticules on the characteristics and maturity in tissue-engineered stem cell-derived retinal pigment epithelium sheets

Authors: Gu Jianing, Su Zhanyu, Wang Yini, Chen Yuexi, Cui Zekai, Li Shengguo, Ding Chengcheng, Sheng Wang, Li Kangjun, Tang Shibo, Chen Jiansu

Background: Recent advances in clinical trials have involved the transplantation of induced retinal pigment epithelium (iRPE) cells from stem cells in creating a functional monolayer that mimics the characteristics of natural adult RPE cells. One method of achieving this goal is through the use of tissue engineering. In this research, decellularised femtosecond laser intrastromal lenticules (dfLEN) were employed as a scaffold for cultivating a bioengineered iRPE monolayer sheet. Methods: iRPE cells were obtained by differentiating induced pluripotent stem cells (iPSC). These cells were then seeded on decellularized FLI-lenticules (dfLEN). The functionality, characterization, and oxidative stress of iRPE cultured on dfLEN were compared with those cultured on plates (TCP) using various assays such as immunofluorescence (IF), Edu, CCK8, ELISA, DFCH-DA, and JC-1. Additionally, RNA-seq assays and electron microscope (SEM and TEM) were used to test the iRPE characteristic on engineered dfLEN. Finally, we evaluated the biocompatibility of iRPE-dfLEN sheets by transplanting them into the subretinal space of New Zealand white rabbits. Results: The iRPE cells cultured on dfLEN exhibited morphology and physiology similar to that of native RPE tissue. The dfLEN not only increased the resistance capacity of iRPE cells but also improved their functional properties compared to TCP. In addition, our results indicate that dfLEN enhances the expression of genes associated with cilium assembly, resulting in notable improvements in ciliogenesis in iRPE cells. Finally, the dfLEN-iRPE sheets demonstrated favorable biocompatibility and some viability when transplanted into the subretinal space of rabbits for a period of 14 days.

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The influence of femtosecond laser intrastromal lenticules on the characteristics and maturity in tissue-engineered stem cell-derived retinal pigment epithelium sheets

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Original ResearchVol. 16, None • pp. 527DOI: 10.1186/s13287-025-04627-5

Transcriptomic insights and feeder-free culturing of porcine expanded potential stem cells from cloned embryos

Authors: Lian Cai, Mirae Kim, Hyerin Choi, Haneul Kim, Sang-Hwan Hyun, Eunhye Kim

Background Generating expanded potential stem cells from cloned porcine embryos (pEPSCsNT) represents a notable advancement in regenerative medicine and agricultural biotechnology. However, challenges, including low derivation efficiency, limited understanding of transcriptomic features, and unknown feasibility of culturing under feeder-free conditions, remain. This study aimed to generate pEPSCs using blastocysts derived from parthenogenetic activation, in vitro fertilization, and somatic cell nuclear transfer (SCNT) using a modified culture system. Methods We derived pEPSCNT lines using an optimized culture system. We characterized the pEPSC lines from all three origins by analyzing pluripotent marker expression, performing karyotyping, and assessing their differentiation potential into the three germ layers. Furthermore, we performed a comparative transcriptomic analysis using in vivo and cloned embryo data, with a major focus on cell lines derived from SCNT (pEPSCsNT). We optimized feeder-free culture conditions for the pEPSCNT line and derived the pEPSCNT lines using an optimized culture system with an efficiency of ~14%. Results The cells were closely correlated with 8-cell to morula-stage embryos and exhibited significant enrichment of EPSC signature genes, suggesting a unique pluripotent state relatively close to the naïve state, specifically within a formative state. The pEPSCsNT possessed broad differentiation capacity, indicative of Hippo signaling pathway enrichment, blastocyst-like structure formation ability, and potential differentiation into trophoblast lineage cells. Conclusions Our modified culture medium combined with the 2× Matrigel coating system facilitated the transition to feeder-independent culture conditions. These findings facilitate the establishment of a feeder-free culture system while preserving pluripotency and differentiation potential.

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Transcriptomic insights and feeder-free culturing of porcine expanded potential stem cells from cloned embryos

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Original ResearchVol. 16, Issue 1 • pp. 609DOI: 10.1186/s13287-025-04755-y

Apremilast improves cardiomyocyte cohesion and arrhythmia in different models for arrhythmogenic cardiomyopathy

Authors: Konstanze Stangner, Orsela Dervishi, Janina Kuhnert, Carl Wendt, Soumyata Pathak, Maria Shoykhet, Silvana Olivares-Florez, Sina Moztarzadeh, Jens Opsteen, Ni Luh Cathrin Suniasih Wohlfarth, Ruth Biller, Elisabeth Graf, Dominik S. Westphal, Tatjana Williams, Brenda Gerull, Tomo Šarić, Sunil Yeruva, Jens Waschke

Background Arrhythmogenic cardiomyopathy (ACM) is a genetically inherited desmosome heart disease leading to life-threatening arrhythmias and sudden cardiac death. Currently, ACM treatment paradigms are merely symptom targeting. Recently, apremilast was shown to stabilize keratinocyte adhesion in the desmosomal disease pemphigus vulgaris. Therefore, this study investigated whether apremilast can be a therapeutic option for ACM. Methods Human induced pluripotent stem cells from a healthy control (hiPSC) and an ACM index patient (ACM-hiPSC) carrying a heterozygous desmoplakin (DSP) gene mutation (c.2854G > T, p.Glu952Ter), confirmed by whole exome sequencing (WES), were established. Cyclic-AMP ELISA, dissociation assay, immunostaining, and Western blotting analyses were performed in human iPSC-derived cardiomyocytes (hiPSC-CMs), murine HL-1 cardiomyocytes, and cardiac slices derived from wild-type (WT) mice, plakoglobin (PG, Jup) knockout (Jup−/−) (murine ACM model) or PG Serine 665 phosphodeficient (JUP-S665A) mice. Microelectrode array (MEA) analyses in ventricular cardiac slices and Langendorff heart perfusion were performed to analyze heart rate variability and arrhythmia. Results ACM-hiPSC derived cardiomyocytes (ACM-hiPSC-CMs) revealed a significant loss of cohesion, which was rescued by apremilast. Further, treatment with apremilast strengthened basal cardiomyocyte cohesion in HL-1 cells and WT murine cardiac slices, paralleled by phosphorylation of PG at Serine 665 in human and murine models. In HL-1 cells, apremilast in addition activated ERK1/2, inhibition of which abolished apremilast-enhanced cardiomyocyte cohesion. Further, dissociation assays in slice cultures from JUP-S665A and Jup−/− mice revealed that PG is crucial for apremilast's effects. Additionally, apremilast reduced arrhythmic events in ventricular cardiac slices and Langendorff-perfused hearts. Conclusion Apremilast improves cardiomyocyte cohesion and reduces arrhythmia in different models of ACM, suggesting a novel therapeutic strategy for this disease.

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Apremilast improves cardiomyocyte cohesion and arrhythmia in different models for arrhythmogenic cardiomyopathy

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Original ResearchVol. 16, None • pp. 136DOI: 10.1186/s13287-025-04168-x

Reviving hope: unlocking pancreatic islet immortality by optimizing a trehalose-based cryopreservation media and cell-penetrating peptide

Authors: Zakieh Samsonchi, Roshanak Amirian, Lobat Tayebi, Hossein Derakhshankhah, Zhila Izadi, Ensiyeh Hajizadeh-Saffar

Background Diabetes mellitus remains a pervasive global health concern, urging a deeper exploration of islet transplantation as a potential enduring solution. The efficacy of this therapeutic approach pivots on the precision of cryopreservation techniques, ensuring both the viability and accessibility of pancreatic islets. This study delves into the merits of cryopreserving these islets using the disaccharide trehalose, accompanied by an inventive strategy involving poly L proline (PLP) as a cell-penetrating peptide to overcome the cryoprotectant limitations inherent to trehalose. Methods In our experiments with rat islets, we conducted meticulous viability assessments for fresh and frozen samples. We employed a spectrum of methods, including live/dead staining, insulin/glucagon staining, and measurement of reactive oxygen species (ROS) levels. To gauge functional integrity, we executed glucose-stimulated insulin secretion tests. Subsequently, we transplanted thawed islets into diabetic mice to scrutinize their performance in clinically relevant conditions. Results Our study yielded compelling results, affirming the successful cryopreservation of pancreatic islets using trehalose and PLP. Viability, as corroborated through live/dead and insulin/glucagon staining, underscored the sustained preservation of frozen islets. Moreover, these preserved islets exhibited functional integrity by releasing insulin responsively to glucose stimulation. Significantly, upon transplantation into diabetic mice, the thawed islets proficiently restored euglycemia, evidenced by a substantial reduction in fasting blood glucose and an enhanced glucose tolerance. Conclusion Our findings accentuate the potential of trehalose and PLP as sophisticated cryoprotectants for preserving pancreatic islets. Beyond highlighting viability and functionality, the preserved islets demonstrated a remarkable capacity to restore euglycemia post-transplantation. This research holds promise in addressing the inherent limitations of islet transplantation, particularly in the realm of Type 1 diabetes treatment.

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Reviving hope: unlocking pancreatic islet immortality by optimizing a trehalose-based cryopreservation media and cell-penetrating peptide

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Original ResearchVol. 16, None • pp. 524DOI: 10.1186/s13287-025-04655-1

A GelMA/polydopamine hydrogel with PTH and osteogenically stimulated alveolar mucosa-derived stem cells promotes bone regeneration in MRONJ-affected wounds

Authors: Che-Chang Tu, Ming-Hsu Chen, Guan-Yu Lan, Yu-Ting Lin, Yu-Tse Lin, Wei-Chiu Tai, Jiashing Yu, Po-Chun Chang

Background Medication-related osteonecrosis of the jaw (MRONJ) is a serious complication in patients taking bisphosphonates. This study aimed at developing a mesenchymal stem cell-based strategy to reduce the incidence of MRONJ and recover regeneration capability of MRONJ-affected wounds by using a gelatin methacryloyl/polydopamine hydrogel (GelMA/PD) to adhere alveolar mucosa-derived stem cells (AMCs) on the bone surface, with the osteogenically stimulated AMCs modulated by microRNA (miR) transfection, and the osteoanabolic environment activated by parathyroid hormone (PTH). Methods GelMA/PD was synthesized by photo-crosslinking, and the incorporation of PD onto GelMA as well as mechanical properties were assessed. Rat AMCs were isolated, and the stemness was characterized. AMCs were osteogenically stimulated by miR transfection. Maxillary osteotomy was created in rats administrated with zoledronic acid and dexamethasone to simulate MRONJ-affected wounds, and osteotomy in rats without ZA served as healthy controls. Wounds were unfilled or filled with GelMA/PD alone, GelMA/PD with AMCs (GA), GelMA/PD with OAMCs (GO), or GelMA/PD with OAMCs and PTH (PO), and were assessed by gross observation, micro-CT imaging, histology, and immunohistochemistry for osteoblast-osteoclast coupling. Results GelMA/PD exhibited modestly decreased compressive strength and superior adhesion strength compared with GelMA. AMCs were double positive for CD73 and CD90, showed trilineage differentiation capability, and were osteogenically stimulated by miR-218 transfection. Among MRONJ-affected wounds, soft tissue coverage was accelerated, with reduced sequestra and significantly greater bone volume in PO group (38.46 ± 10.02%) relative to unfilled group (21.81 ± 6.18%), and osteoblast-osteoclast coupling was evident in GO and PO groups. Soft tissue recovery, inflammation reduction, and matrix deposition on defect surfaces were more prominent in PO group.

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A GelMA/polydopamine hydrogel with PTH and osteogenically stimulated alveolar mucosa-derived stem cells promotes bone regeneration in MRONJ-affected wounds

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Original ResearchVol. 16, None • pp. 571DOI: 10.1186/s13287-025-04665-z

Extracellular vesicle bioactivity and potential for clinical development are determined by mesenchymal stromal cell clonal subtype

Authors: Savvas Ioannou, Alasdair G. Kay, Andrew P. Stone, Emma Rand, Samuel Elberfeld, William Bolton, Tony Larson, Rachel E. Crossland, Oksana Kehoe, David A. Mentlak, Xiao-Nong Wang, Chris MacDonald, Paul G. Genever

Background Mesenchymal stromal cells (MSCs) have been used in numerous clinical trials but very few reach phase 3 or market authorisation. Progress is often hampered by the use of non-clonal, heterogeneous and uncharacterised MSC cultures and lack of mechanistic understanding. There is limited evidence of MSC engraftment in vivo and disease resolution may be the result of the paracrine effects of the MSC secretome, rather than the cells per se. Extracellular vesicles (EVs) are key components of the MSC secretome and there is growing interest in the use of EVs as cell-free therapies. However, like MSCs, heterogeneity can exist within any therapeutic EV pool. Here we used immortalised clonal MSC lines, termed Y201 and Y202, to examine how MSC phenotype influences EV character and function. Methods EVs were isolated by ultracentrifugation and characterised by nano-sizing, ultrastructural morphometric analysis, western blotting, mass spectrometry and miRNA screening. Bioactivity was determined by phosphorylation of ERK1/2, proliferation and T cell polarisation assays and using two in vivo models of inflammatory disease. Results EVs from Y201 and Y202 MSCs were morphologically similar, however, Y201 EVs were more abundant in EV biomarkers versus Y202 EVs, with an enhanced miRNA and proteomic content. Computational analysis of the Y201 EV proteome identified significant enrichment in matrix-associated proteins, predicted to contribute to an elaborate EV corona particularly abundant in RGD-containing proteins fibronectin and MFG-E8, which was confirmed by western blotting. Y201 EVs, but not Y202 EVs, significantly increased the proliferation of articular chondrocytes in a dose-dependent manner, and the proliferative effect of Y201 EVs was mediated at least in part via an RGD (integrin)-FAK-ERK1/2 axis. Both Y201 and Y202 EV subsets significantly reduced proliferative index scores of activated T cells. However, only Y201 EVs, not Y202 EVs, suppressed disease activity compared to controls in different in vivo models of inflammatory peritonitis and arthritis.

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Extracellular vesicle bioactivity and potential for clinical development are determined by mesenchymal stromal cell clonal subtype

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Original ResearchVol. 16, None • pp. 570DOI: 10.1186/s13287-025-04573-2

Intranasal delivery of DPSC-derived small extracellular vesicles-encased phloroglucinol attenuates non-motor and motor deficits and promotes neurogenesis in an in vivo rat model of Parkinson’s disease

Authors: Kallolika Mondal, Rituparna Ghanty, Anita Mahadevan, Girish Waghmare, Rashmi Santhoshkumar, Nandeesh BN, Indrani Datta

Background Parkinson’s disease (PD) is characterized by dopaminergic (DA) neuron degeneration in the substantia nigra pars compacta (SNpc) driven by oxidative stress, inflammation, and impaired neurogenesis. Phloroglucinol, a polyphenolic antioxidant, has demonstrated neuroprotective effects in PD models but suffers from limited clinical applicability due to poor blood-brain barrier (BBB) permeability. Small extracellular vesicles (sEV) derived from dental pulp stem cells (DPSCs) exhibit neuroprotective and immunomodulatory properties and serve as promising vehicles for targeted drug delivery across the BBB. This study aimed to evaluate the therapeutic efficacy of intranasally administered sEV-encased phloroglucinol (sEV-Phl) in a chronic MPTP rat model of PD. Methods DPSC-derived sEV were isolated via density gradient ultracentrifugation and characterized using Transmission Electron Microscopy (TEM), Dynamic-Light-Scattering (DLS), and CD marker expression. Phloroglucinol was encased in sEV (sEV-Phl) using sonication. Antioxidant properties were tested in vitro using an H2DCF.DA assay in SH-SY5Y cells exposed to 6-OHDA. Chronic MPTP-treated male Wistar rats received intranasal sEV-Phl, with motor and non-motor behaviours evaluated up to 4-weeks post-MPTP treatment. TH-positive neurons, neurogenesis (Ki67, BrdU and FOXA2), lipid-peroxidation, and neurotransmitter-levels were analyzed. sEV biodistribution was tracked via near-infrared imaging and localization in neuronal and glial cells was confirmed with PKH-26 labelling, with confocal-imaging further verifying localization in neuronal and glial cells. TNF-α expression was assessed as a marker of neuroinflammation. Results sEV displayed high purity and homogeneity. sEV-Phl significantly reduced oxidative stress both in vitro and in vivo, as indicated by decreased ROS and lipid peroxidation levels. sEV-Phl treated MPTP rats demonstrated marked improvement in motor and non-motor behaviours compared to MPTP rats. Immunohistochemical analysis revealed

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Intranasal delivery of DPSC-derived small extracellular vesicles-encased phloroglucinol attenuates non-motor and motor deficits and promotes neurogenesis in an in vivo rat model of Parkinson’s disease

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Original ResearchVol. 16, None • pp. 206DOI: 10.1186/s13287-025-04322-5

Nano-zinc oxide (nZnO) targets the AMPK-ULK1 pathway to promote bone regeneration

Authors: Xiu Chen, Zhenkun Weng, Hongchao Zhang, Jian Jiao, Jingjia Liang, Jin Xu, Dongmei Wang, Qian Liu, Qing Yan, Aihua Gu

Background Nano-zinc oxide (nZnO) has attracted significant attention in bone tissue engineering due to its antibacterial properties, anti-inflammatory effects, biocompatibility, and chemical stability. Although numerous studies have demonstrated the enhancement of osteogenic differentiation by nZnO-modified tissue engineering materials, the underlying mechanisms remain poorly characterized. Methods This study aimed to identify the molecular mechanisms how nZnO promoted osteogenic differentiation and bone regeneration using transcriptome analysis, drug intervention, and shRNA knockdown techniques, etc. First, the study evaluated the in vivo effects of gelatin methacryloyl (GelMA) containing nZnO on bone regeneration using a mouse calvarial defect model. The impact of nZnO exposure on the osteogenic differentiation of mesenchymal stem cells (MSCs) was then assessed. The combined treatment of nZnO and MSCs in GelMA for bone regeneration was assessed in the mouse calvarial defect model thereafter. Results nZnO induced osteoblastic differentiation to promote bone regeneration. nZnO activated the AMP-dependent protein kinase (AMPK)-ULK1 signals to stimulate autophagosomes formation and facilitate autophagy flow, which was the essential pathway to induce osteogenic differentiation. The combined treatment of MSCs and nZnO significantly enhanced bone regeneration in calvarial defect mice. Conversely, AMPK inhibitor Compound C (C.C) reversed the effects on autophagy flow and osteogenic potentiality induced by nZnO. Conclusions These results highlight that nZnO can regulate bone regeneration by activating autophagy through the AMPK/ULK1 signaling pathway, which may provide a novel therapeutic strategy for addressing bone defects using nZnO.

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Nano-zinc oxide (nZnO) targets the AMPK-ULK1 pathway to promote bone regeneration

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Original ResearchVol. 16, None • pp. 483DOI: 10.1186/s13287-025-04578-x

BACH1 recruits STAT3 to enhance leukemia inhibitory factor receptor activity and augments the self-renewal capacity of mouse embryonic stem cells

Authors: Jinghua Ma, Siyu Ma, Cong Niu, Siqing Wang, Xiangxiang Wei, Dan Meng, Xiuling Zhi, Jieyu Guo

Background Genomic studies have linked single nucleotide variants in the enhancer region of the leukemia inhibitory factor receptor (Lifr) gene to chromatin accessibility and the regulation of self-renewal in mouse embryonic stem cells (mESCs). However, the underlying mechanisms remain unclear. This study investigates the role of the transcription factor BTB and CNC homology 1 (BACH1) in regulating the Lifr enhancer and its impact on mESC pluripotency. Methods We performed RNA-sequencing (RNA-seq) to assess the impact of Bach1 knockout on gene expression in mESCs. Additionally, chromatin immunoprecipitation (ChIP), co-immunoprecipitation (co-IP), and luciferase reporter gene analysis were employed to investigate the mechanism by which BACH1 regulates Lifr expression. Results Genomic analyses identified BACH1 binding at the Lifr enhancer proximal to rs50454566 in mESCs. Integrated single-cell RNA sequencing (scRNA-seq) data revealed co-upregulation of Bach1 and Lifr in inner cell mass (ICM) cells. RNA-seq analyses demonstrated that Bach1 depletion attenuated Lifr expression and impeded LIFR-signal transducer and activator of transcription 3 (STAT3) signaling. Mechanistically, BACH1 recruited STAT3 to the Lifr enhancer, driving Lifr transcription and facilitating the LIFR-STAT3 signaling pathway, thereby enhancing mESC self-renewal. Conclusion Our findings demonstrate that BACH1 enhances Lifr enhancer activity by recruiting STAT3 and activates the LIFR-STAT3 signaling pathway by promoting the LIFR expression, thereby maintaining mESC self-renewal.

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BACH1 recruits STAT3 to enhance leukemia inhibitory factor receptor activity and augments the self-renewal capacity of mouse embryonic stem cells

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Original ResearchVol. 16, None • pp. 399DOI: 10.1186/s13287-025-04480-6

From inflammation to healing: the crucial role of GPR91 activation and SDH inhibition in chronic diabetic wound recovery

Authors: Hengdeng Liu, Shixin Zhao, Hanwen Wang, Xuefeng He, Suyue Gao, Minmin Su, Miao Zhen, Shuying Chen, Lei Chen, Julin Xie

Background Diabetic foot ulcers (DFU) typically exhibit impaired healing due to dysregulated re-epithelialization and excessive inflammation. Succinate, a key metabolic intermediate, is now understood to regulate inflammation through G Protein-Coupled Receptor 91 (GPR91) and succinate dehydrogenase (SDH), although its role in DFU remains unclear. Methods Co-cultures of M2 macrophages and epithelial cells, along with clinical samples, were used to analyze the expression of GPR91 and SDH. Functional assays were performed using high glucose (HG)-treated M2 macrophages (HG-M2) and an in vivo model. Cytokine and growth factor levels in cell supernatant were measured, and molecular mechanisms were explored via qRT-PCR, flow cytometry, and western blot analysis. Results Elevated glucose concentrations increased succinate levels and disrupted M2 macrophage–epidermal stem cells (EpSCs) interactions. GPR91 knockdown worsened HG-M2 dysfunction, while GPR91 overexpression (OE-GPR91) enhanced anti-inflammatory responses and reduced succinate. OE-GPR91-conditioned medium preserved EpSCs stemness and promoted migration mediated by hepatocyte growth factor (HGF). SDH inhibition (via Dimethyl malonate, DMM) boosted M2 macrophage activity by reducing reactive oxygen species (ROS) and upregulating Gpr91 expression. Mechanistically, GPR91 activated the pAkt/pGSK3β/β-catenin pathway, while DMM enhanced M2 macrophage function via the PI3K-Akt/pERK1/2 pathway. Conclusions GPR91 upregulation and SDH inhibition improve HG-M2 macrophage function, reduce inflammation, and enhance HGF-mediated EpSCs repair. Targeting both pathways may represent a promising approach to promote DFU healing.

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From inflammation to healing: the crucial role of GPR91 activation and SDH inhibition in chronic diabetic wound recovery

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Original ResearchVol. 16, None • pp. 53DOI: 10.1186/s13287-025-04154-3

MSCs with upregulated lipid metabolism block hematopoietic stem cell differentiation via exosomal CTP-1A in MDS

Authors: Chunlai Yin, Xue Yan, Jinyi Ren, Cheng Zhang, Jiaqing Liu, Zilong Wang, Jing Liu, Weiping Li, Xia Li

Background Myelodysplastic syndrome (MDS) is a clonal disorder of hematopoietic stem cells (HSCs), characterized by ineffective hematopoiesis and a high risk of progression to acute myeloid leukemia. Elucidating the mechanism underlying the dysfunction of MDS-HSCs is crucial for exploring the pathogenesis of the syndrome. While previous studies have implicated mesenchymal stem cells (MSCs), a principal component of the bone marrow (BM) microenvironment, in the inhibition of normal hematopoiesis, the precise molecular mechanisms have not been fully elucidated. In this study, we investigated the effects of MSCs from MDS patients on hematopoietic functions of HSCs from a metabolic perspective. Methods MSCs were isolated from BM of MDS patients. The proliferation, apoptosis, differentiation and support for hematopoiesis of these cells were analyzed using CCK-8 assay, FC and induction medium and CFU (colony forming units) assay, respectively. Expression levels of metabolic molecules were used as indicators to screen MSCs with different metabolic pathways and were detected by RT-PCR and Western blotting. Exosome derived from MSCs were isolated from the culture supernatant and confirmed by Transmission Electron Microscope, Dynamic Light Scattering and Western blotting. The effects of these exosomes on HSCs were analyzed using the same methods as those used to assess MSCs function. Results Our findings demonstrated that MDS-MSCs exhibited significant functional impairments, including reduced proliferation, impaired differentiation, diminished support for hematopoiesis, and increased apoptosis. Notably, we observed an upregulation of lipid metabolism in these MSCs, which appears to contribute to their dysfunction. Intriguingly, the aberrant lipid metabolic profile can be effectively reversed by the administration of etomoxir (ETO), an inhibitor of carnitine palmitoyltransferase 1A (CPT-1A). Furthermore, MSCs with enhanced lipid metabolism could transmit this dysfunction to HSCs through the secretion of exosomes that are enriched in CPT-1A. Conclusions We suggest that the MDS BM microenvironment disrupts MSCs metabolism by increasing the expression of CPT-1A, which impairs the ability to support normal HSCs. Interestingly, the suppressive effect is mediated by exosomes rich in CPT-1A, which derived from MSCs. These findings provide novel insights into MDS MSCs-metabolism-Exosome axis in ineffective hematopoiesis and offer new strategies for the treatment of MDS.

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MSCs with upregulated lipid metabolism block hematopoietic stem cell differentiation via exosomal CTP-1A in MDS

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Original ResearchVol. 16, None • pp. 376DOI: 10.1186/s13287-025-04504-1

Small extracellular vesicles secreted from TGF-β1-licensed mesenchymal stromal cells reduce inflammation-associated injury following corneal alkali burn

Authors: Ellen Donohoe, Aoife Canning, Eanna Johnston, Seyedmohammad Moosavizadeh, Jiemin Wang, Martin Leahy, Oliver Treacy, Aideen E. Ryan, Thomas Ritter

Background It is well established that the mesenchymal stromal cell (MSC) therapeutic potency can be enhanced by cytokine pre-activation or licensing. However, its effects on therapeutic efficacy of small extracellular vesicles (MSC-sEV) have not yet been well established. Here we report on two different cytokine licensing strategies, using either a pro-inflammatory or anti-inflammatory cytokine and evaluate their therapeutic potency in vitro and in a preclinical model of corneal chemical burn. Methods BALB/c MSCs were cultured with no supplement, recombinant IFNγ, or recombinant TGFβ1 for 72 h. sEV, sEVIFNγ, and sEVTGFβ were then isolated from conditioned medium of parental cells by a combination of ultrafiltration and size exclusion chromatography. Following isolation MSC-sEV were thoroughly characterized for size, marker expression and therapeutic efficacy. To evaluate their immunomodulatory capacity, both naïve and licensed MSC-sEV were tested in in vitro macrophage and T cell assays and in a preclinical corneal injury model. Results Relative to unlicensed sEV, sEVIFNγ exhibited increased expression of MHC I and PD-L1 on their surface, whereas sEVTGFβ expressed higher levels of CD44, CD29, and CD73. For immunomodulatory capacity, only sEVTGFβ was found to reduce macrophage expression of MHC II and CD80 and induced the secretion of anti-inflammatory macrophage cytokines. sEVTGFβ were also found to increase Treg expansion and FOXP3 expression. Given the superior efficacy observed of sEVTGFβ in vitro, this product was evaluated in a preclinical mouse model of corneal chemical burn. sEVTGFβ were applied either topically (day 0, 1, and 3) or subconjunctivally (day 0, and 3), and mice were monitored for 14 days. sEVTGFβ ameliorated burn-induced structural damage and accelerated restoration of normal corneal thickness, compared to PBS-treated controls. sEVTGFβ also resulted in reduced inflammatory mediators (IL-1β, iNOS) and minimised levels of fibrosis-associated collagen in the cornea. Mice that received subconjunctival, but not topical, administration of sEVTGFβ exhibited regulatory immune cell profiles with reduced pro-inflammatory-

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Small extracellular vesicles secreted from TGF-β1-licensed mesenchymal stromal cells reduce inflammation-associated injury following corneal alkali burn

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Original ResearchVol. 16, None • pp. 105DOI: 10.1186/s13287-025-04245-1

Apoptotic vesicles derived from bone marrow mesenchymal stem cells increase angiogenesis in a hind limb ischemia model via the NAMPT/SIRT1/FOXO1 axis

Authors: Jinxing Chen, Zekun Shen, Bingyi Chen, Shuang Liu, Yifan Mei, Kai Li, Ziyang Peng, Chaoshuai Feng, Weiyi Wang, Shaoying Lu

Background Chronic limb-threatening ischemia (CLTI) is the most severe form of peripheral arterial disease (PAD). Mesenchymal stem cell (MSC) transplantation holds promise as a treatment for CLTI; however, the harsh local environment poses challenges to its effectiveness. Apoptotic vesicles (ApoVs) are extracellular vesicles produced by cells undergoing apoptosis, and they can carry various biomolecules from their parent cells, including proteins, RNA, DNA, lipids, ions, and gas neurotransmitters. ApoVs play significant roles in anti-inflammatory responses, anti-tumor activities, and tissue regeneration through intercellular communication, and they have demonstrated potential as drug carriers. In this study, we investigated the potential of bone marrow stem cell (BMSC)-derived ApoVs for treating CLTI. Methods In vivo, we explored the therapeutic effect of ApoVs on a hindlimb ischemia model through Laser Doppler, matrigel plug assay, and histological analysis. In vitro, we analyzed the effects of ApoVs on the proliferation, migration, and angiogenesis of HUVECs and explored the uptake process of ApoVs. In addition, Proteomic analysis, western blotting, quantitative real-time PCR, shRNA, and siRNA were used to analyze ApoVs-induced HUVECs activation and downstream signaling pathways. Results BMSCs transplantation showed improvement in a hind limb ischemia model, and this effect still exists after apoptosis of BMSCs. Subsequently, ApoVs of BMSCs were isolated and found to improve mouse hind limb ischemia in vivo. In vitro, ApoVs can be ingested by HUVECs through dynamin-, clathrin-, and caveolin-mediated endocytosis and promote its proliferation, migration, and angiogenesis. Mechanistically, ApoVs transferred NAMPT to HUVECs, therefore activating the NAMPT/SIRT1/FOXO1 axis, influencing the transcriptional activity of FOXO1, and promoting angiogenesis. Conclusions Our results demonstrate that the transplanted BMSCs can ameliorate hindlimb ischemia by releasing ApoVs during apoptosis. The main mechanism of this effect is promoting the proliferation, migration, and angiogenesis of endothelial cells via the NAMPT/SIRT1/FOXO1 axis.

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Apoptotic vesicles derived from bone marrow mesenchymal stem cells increase angiogenesis in a hind limb ischemia model via the NAMPT/SIRT1/FOXO1 axis

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Original ResearchVol. 16, Issue 472 • pp. 1-8DOI: 10.1186/s13287-025-04608-8

Integrin signaling pathways in mesenchymal stem cells

Authors: Dafina Najwa Mohd Arizam, Fazlina Nordin, Azlina Ahmad, Khairul Bariah Ahmad Amin Noordin

This review provides an overview of the integrin signaling pathways and their roles in mesenchymal stem cell differentiation into adipocytes, chondrocytes, and osteoblasts. In these three differentiated cells, the cell extracellular matrix plays an important role in regulating the integrin signaling pathway, as the presence of growth factors and other molecules in the extracellular matrix will affect the cell differentiation. The focus of this review is to elucidate the role of the integrin signaling pathway in adipogenesis, chondrogenesis, and osteogenesis, highlighting its diverse contributions to tissue homeostasis and repair. By synthesizing current knowledge, this paper aims to inspire further research into the therapeutic potential of targeting integrin pathways in stem cell-based tissue engineering.

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Integrin signaling pathways in mesenchymal stem cells

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Original ResearchVol. 16, None • pp. 403DOI: 10.1186/s13287-025-04532-x

Human embryonic stem cell-derived Sertoli cells as an immune modulator of cell transplantation therapy in a diabetic mice model

Authors: Jeoung Eun Lee, Chang Woo Lee, A-Reum Han, Jina Kim, Dong Ryul Lee

Objective Sertoli cells (SCs) are somatic cells that are a part of the seminiferous tubules in the testes and support germ cell development and maturation. Additionally, SCs play another role in protecting male germ cells from immune destruction via the formation of the blood-testis barrier and the secretion of several immunoregulatory factors. Based on these characteristics, SCs have been suggested to create a tolerogenic environment to protect co-transplanted cells as immune modulators. Because mature SCs are quiescent somatic cells and show lower proliferation activity in vitro, it is difficult to obtain the number of human cells needed for clinical applications. Materials and methods We established a protocol for mass production of SCs from human ESCs (hESC-SCs) and their functional properties were analyzed in vitro and in diabetic-induced mice after their co-transplantation with human insulin-secreting cells. Results hESC-SCs were successfully produced via a stepwise differentiation protocol. In addition, a mass culture method was established to secure the number of hESC-SCs available for cell therapy. hESC-SCs obtained from in vitro derivation highly express marker genes of SCs, such as GATA4, SOX9, CLDN11, and AR, and have shown immune-modulation activity similar to that of human bone marrow-mesenchymal stem cells. In diabetic-induced mice subcutaneously co-transplanted with EndoC-βH1 cells (insulin-secreting cells) and hESC-SCs, lower blood glucose levels were maintained for 6 months than in those transplanted with EndoC-βH1 cells alone. Conclusions We believe that hESC-SCs could be useful tool for securing cell therapy to treat human diseases in the future.

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Human embryonic stem cell-derived Sertoli cells as an immune modulator of cell transplantation therapy in a diabetic mice model

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Original ResearchVol. 16, None • pp. 300DOI: 10.1186/s13287-025-04401-7

Synergistic potential of bone marrow mesenchymal stem cells and miR181-a combinational therapy against multiple sclerosis

Authors: Xin Xiu, Sijia Chen, Yumei Liu, Bo Sun, Hulun Li, Sifan Zhang, Xixi Yang, Yu Wei, Xichen Peng, Yan Wang, Yanping Wang, Junfeng Wu, Yao Zhang, Lili Mu, Qingfei Kong, Xijun Liu

Background: Multiple sclerosis (MS) is a progressive autoimmune disease characterized by massive inflammatory infiltration, demyelination, and subsequent axonal injury and neuronal damage in the central nervous system (CNS). The etiology of MS remains unclear and there is not yet a definitive therapeutic schedule for the disease. Bone marrow mesenchymal stem cells (BMSCs), exhibiting neuroimmune-modulatory functions to alleviate various autoimmune diseases, show great potential in the treatment of MS. However, the instability of BMSCs-mediated immunosuppression in vivo has limited their application. MiR181-a, a positive regulator of immune balance, which has a preference for T cells and B cells differentiation, but degrade rapidly upon entering systemic circulation due to their unstable molecular structure. Methods: We propose a synergistic therapy approach that combines the penetrative targeting capability of BMSCs with the immuno-modulatory effects of miR181-a by overexpressing miR181-a to BMSCs through lentivirus packaging system. With this strategy, on the basis of the establishment of the experimental autoimmune encephalomyelitis (EAE) model, miR181-a overexpressing BMSCs (miR181a-BMSCs) would have a stronger immuno-modulatory treatment benefit, in terms of attenuating MS development. Results: Indicate that this method prolongs the modulatory effects of BMSCs and resulted in significantly enhancements of the proliferation of regulatory B cells (Bregs), regulatory T cells (Tregs) and the inhibition of Th17 cells compared to the traditional BMSCs group. Moreover, 10-fold miRNA’s concentration in the exosome of miR181a-BMSCs, leading to an increased duration of miRNAs to exert their biological effects. By immunotherapy and synergistic treatment, the effectiveness of the treatment is significantly enhanced, showing consistent results in different groups of the animal model.

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Synergistic potential of bone marrow mesenchymal stem cells and miR181-a combinational therapy against multiple sclerosis

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Original ResearchVol. 16, Issue 1 • pp. 84DOI: 10.1186/s13287-025-04229-1

OCT4 translationally promotes AKT signaling as an RNA-binding protein in stressed pluripotent stem cells

Authors: Wenjie Chen, Xinyu Chen, Cheng Chen, Shiqi She, Xia Li, Lina Shan, Xiaobing Zhang, Songsong Dan, Yisha Wang, Yan-Wen Zhou, Qingyi Cao, Wenxin Wang, Jianwen Hu, Yaxun Wei, Yaqiang Xue, Yi Zhang, Songying Zhang, Ying-Jie Wang, Bo Kang

Background Despite numerous studies addressing the molecular mechanisms by which pluripotent stem cells (PSCs) maintain self-renewal and pluripotency under normal culture conditions, the fundamental question of how PSCs manage to survive stressful conditions remains largely unresolved. Post-transcriptional/translational regulation emerges to be vital for PSCs, but how PSCs coordinate and balance their survival and differentiation at translational level under extrinsic and intrinsic stress conditions is unclear. Methods The high-throughput sequencing of cross-linking immunoprecipitation cDNA library (HITS-CLIP) was employed to decipher the genome-wide OCT4-RNA interactome in human PSCs, a combined RNC-seq/RNA-seq analysis to assess the role of OCT4 in translational regulation of hypoxic PSCs, and an OCT4-protein interactome to search for OCT4 binding partners that regulate cap-independent translation initiation. By taking the Heterozygous Knocking In N-terminal Tags (HKINT) approach that specifically disrupts the 5'-UTR secondary structure and tagging its protein product of the mRNA from one allele while leaving that from the other allele intact, we examined the effect of disrupting the OCT4/5'-UTR interaction on translation of AKT1 mRNA. Results We revealed OCT4 as a bona fide RNA-binding protein (RBP) in human PSCs that bound to the 5'-UTR, 3'-UTR and CDS regions of mRNAs. Multiple known proteins participating in IRES-mediated translation initiation were detected in the OCT4-protein interactome, and a combined RNC-seq/RNA-seq analysis further confirmed a crucial role of OCT4 in translational regulation of PSCs in response to hypoxic stress. Remarkably, OCT4 bound to the GC-rich elements in the 5'-UTR of AKT1 and multiple PI3K/AKT-pathway-gene mRNAs, and promoted their translation initiation via IRES-mediated pathways under stress conditions. Specifically disrupting the AKT1 mRNA 5'-UTR structure and the OCT4/5'-UTR interaction by the HKINT approach significantly reduced the translation level of AKT1 that led to a higher susceptibility of PSCs to oxidative stress-induced apoptotic death and prioritized differentiation toward ectoderm and endoderm. Conclusions Our results reveal OCT4 as an anti-stress RBP for translational regulation that critically coordinates the survival and differentiation of PSCs in response to various stressors.

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OCT4 translationally promotes AKT signaling as an RNA-binding protein in stressed pluripotent stem cells

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Original ResearchVol. 16, None • pp. 521DOI: 10.1186/s13287-025-04642-6

A traditional herbal decoction regulates skeletal muscle satellite cell osteogenesis and myogenesis for repairing osteosarcopenic fractures via β-catenin

Authors: Zhenxiong Jin, Weiwei Da, Yi Shen, Yongjian Zhao, Hao Xu, Hongbo Wan, Xuequn Wu, Xiang Gao, Yan Li, Qi Shi, Dezhi Tang

Introduction: Osteosarcopenic fractures, an emerging geriatric syndrome characterized by sarcopenia-osteoporotic fractures coexistence, delayed fracture healing, and elevated risk of re-fracture. Limited research has investigated the mechanisms by which skeletal muscle satellite cells (SMSCs) promote muscle regeneration and osteoporotic fracture healing. The aim of this study was to investigate the impact of a traditional herbal decoction (HD), the Invigorate the Spleen and Tonify the Kidney Formula, on SMSC regulation, muscle regeneration, and fracture healing. Method: Using conditional knockout mice, the role of SMSCs in promoting fracture healing and mitigating sarcopenia was evaluated by visualizing the fracture area and surrounding muscle tissue. The signaling pathways involved were comprehensively analyzed using a combination of Western blotting, real-time PCR analysis, immunohistochemical staining, and immunofluorescent staining. And the key elements and compounds facilitating osteogenesis and myogenesis were identified using HPLC and network pharmacology analysis. Results: This study demonstrated that the herbal decoction mediates the β-catenin signaling pathway, mobilizes SMSCs to migrate to the fracture area, facilitates their osteogenic and myogenic differentiation, and enhances osteoporotic fracture healing. Knockdown of β-catenin in SMSCs in Pax7-CreERT2/+;β-cateninfx/fx conditional knockout mice led to sarcopenia and osteoporosis. Additionally, the herbal decoction significantly increased bone mass, repaired bone microstructure, and promoted muscle fiber remodeling around fractures in mice. Conclusions: These findings provide the first evidence that the HD, as a β-catenin agonist, not only promotes fracture healing by modulating the osteogenic and myogenic effects of SMSCs but also ameliorates sarcopenia.

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$A traditional herbal decoction regulates skeletal muscle satellite cell osteogenesis and myogenesis for repairing osteosarcopenic fractures via β-catenin$

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Original ResearchVol. 16, None • pp. 573DOI: 10.1186/s13287-025-04737-0

Human induced pluripotent stem cells for in vitro modeling of impaired mucociliary clearance in cystic fibrosis lung disease

Authors: Mark-Christian Klassen, Anita Balázs, Janina Zöllner, Nicole Cleve, Laurien Czichon, Laura von Schledorn, Jan Hegermann, Janna C. Nawroth, Doris Roth, Mia Mielenz, Silke Hedtfeld, Frauke Stanke, Tihomir Rubil, Fabio Ius, Danny Jonigk, John W. Hanrahan, Arjang Ruhparwar, Ruth Olmer, Marcus A. Mall, Sylvia Merkert, Ulrich Martin

Severely impaired mucociliary airway function is the primary pathomechanism in Cystic Fibrosis (CF) lung disease. Despite significant advances in CF therapy, there is still a critical need for alternative, individualized treatment options, especially for patients with untreatable CFTR mutations. Although intestinal organoids and primary airway cells are widely used as preclinical models of CF, both systems exhibit limitations with regard to the proper modelling of mucociliary clearance or the availability of sufficient cell quantities. Patient-specific human induced pluripotent stem cells (hiPSCs) are a promising alternative due to their unlimited expansion potential and capacity to differentiate into airway epithelia. However, cellular inhomogeneities in iPSC-derived airway cultures complicated conventional assays that determine CFTR function such as Ussing chamber measurements, and a comprehensive demonstration of CF pathophysiology in hiPSC-derived airway models has been largely lacking. This study provides comprehensive data demonstrating very similar gene expression, (ultra)structure and CFTR function in CF iPSC-derived airway (iALI) and primary airway (pALI) cultures. Addressing current limitations, we have implemented a sensitive, straightforward, and automatable ciliary beat frequency (CBF) assay, which is largely unaffected by inhomogeneities and directly reflects disturbed mucus viscosity and mucociliary transport in CF lung disease. Electron microscopy images confirmed the disease phenotype showing a highly dense and dehydrated mucus layer on top of CF iALI cultures. Furthermore, established CFTR modulator drugs partially rescued the disease phenotype in CF iALI cultures, which validated the utility of iALI cultures as a scalable, patient-specific platform for CF research and personalized drug development.

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Human induced pluripotent stem cells for in vitro modeling of impaired mucociliary clearance in cystic fibrosis lung disease

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Original ResearchVol. 16, None • pp. 291DOI: 10.1186/s13287-025-04396-1

hUMSC-derived exosomes alleviate follicular interstitial cell autophagy by let-7a-5p/AMPK/mTOR axis in POI rats

Authors: Yu Tang, Yu He, Xingyu Huo, Juntong Chen, Maojiao Qian, Haoyu Huang, Yixuan Meng, Lianshuang Zhang, Feibo Xu, Yukun Zhang, Hongchu Bao, Yanlian Xiong

Background One major factor contributing to infertility in women of childbearing age is premature ovarian insufficiency (POI). Exosomes produced from human umbilical cord mesenchymal stem cells (hUMSC-Exos) have drawn a lot of attention lately as a potential treatment for ovarian dysfunction brought on by POI. However, its therapeutic mechanism is still unclear and needs further exploration. Methods POI model was established by intraperitoneal injection of cyclophosphamide (CTX) in female Wistar rats. These POI rats were treated with hUMSC-Exos for one week. In addition to in vivo experiments, in vitro POI models were also established. In vitro experiments, theca interstitial cells (TICs) treated with CTX were exposed to normal as well as let-7a-5p inhibitory hUMSC-Exos. The ovary structure, morphology, endocrine function, and reproductive ability of POI rats were observed by H&E staining and ELISA. Western blot, immunofluorescence staining (IF), and quantitative real-time polymerase chain reaction (qRT-PCR) were used to evaluate the autophagy-related indexes in ovary and TICs of POI rats in each group. Results CTX induced abnormalities of ovarian morphology, structure, endocrine, and reproductive function in rats, and accompanied by autophagy of TICs. Notably, hUMSC-Exos diminishes ovarian structural and functional damage in POI rats and TICs autophagy via targeting the AMPK/mTOR pathway. Furthermore, downregulating let-7a-5p in hUMSC-Exos weakened their ability to prevent TICs autophagy. Conclusions Overall, the findings suggested that hUMSC-Exos improves ovarian function in POI rats by inhibiting TICs autophagy via the let-7a-5p/AMPK/mTOR pathway. Our study provided further evidence that POI patients can benefit from hUMSC-Exos-mediated therapy.

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hUMSC-derived exosomes alleviate follicular interstitial cell autophagy by let-7a-5p/AMPK/mTOR axis in POI rats

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Original ResearchVol. 16, Issue 1 • pp. 81DOI: 10.1186/s13287-025-04202-y

Human spindle-shaped urine-derived stem cell exosomes alleviate severe fatty liver ischemia–reperfusion injury by inhibiting ferroptosis via GPX4

Authors: Shangheng Shi, Cunle Zhu, Shangxuan Shi, Xinqiang Li, Imran Muhammad, Qingguo Xu, Xinwei Li, Ziyin Zhao, Huan Liu, Guangming Fu, Meiying Song, Xijian Huang, Feng Wang, Jinzhen Cai

Background Severe hepatic steatosis can exacerbate Ischemia–reperfusion injury (IRI), potentially leading to early graft dysfunction and primary non-function. In this study, we investigated the heterogeneity of different subpopulations of Urine-derived stem cells (USCs) to explore the most suitable cell subtype for treating severe steatotic liver IRI. Methods This study utilized scRNA-seq and Bulk RNA-seq to investigate the transcriptional heterogeneity between Spindle-shaped USCs (SS-USCs) and Rice-shaped USCs (RS-USCs). Additionally, rat fatty Liver transplantation (LT) model, mouse fatty liver IRI model, and Steatotic Hepatocyte Hypoxia-Reoxygenation (SHP-HR) model were constructed. Extracellular vesicles derived from SS-USCs and RS-USCs were isolated and subjected to mass spectrometry analysis. The therapeutic effects of Spindle-shaped USCs Exosomes (SS-USCs-Exo) and Rice-shaped USCs Exosomes (RS-USCs-Exo) were explored, elucidating their potential mechanisms in inhibiting ferroptosis and alleviating IRI. Results Multiple omics analyses confirmed that SS-USCs possess strong tissue repair and antioxidant capabilities, while RS-USCs have the potential to differentiate towards specific directions such as the kidney, nervous system, and skeletal system, particularly showing great application potential in renal system reconstruction. Further experiments demonstrated in vivo and in vitro models confirming that SS-USCs and SS-USCs-Exo significantly inhibit ferroptosis and alleviate severe fatty liver IRI, whereas the effects of RS-USCs/RS-USCs-Exo are less pronounced. Analysis comparing the proteomic differences between SS-USCs-Exo and RS-USCs-Exo revealed that SS-USCs-Exo primarily inhibit ferroptosis and improve cellular viability by secreting exosomes containing Glutathione Peroxidase 4 (GPX4) protein. This highlights the most suitable cell subtype for treating severe fatty liver IRI. Conclusions SS-USCs possess strong tissue repair and antioxidant capabilities, primarily alleviating ferroptosis in the donor liver of fatty liver through the presence of GPX4 protein in their exosomes. This highlights SS-USCs as the most appropriate cell subtype for treating severe fatty liver IRI.

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Human spindle-shaped urine-derived stem cell exosomes alleviate severe fatty liver ischemia–reperfusion injury by inhibiting ferroptosis via GPX4

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Original ResearchVol. 16, None • pp. 296DOI: 10.1186/s13287-025-04417-z

KRT5high TP63-expressing urothelial basal cells act as a driver to bladder urothelium regeneration in rabbit

Authors: Jiasheng Chen, Mingming Yu, Lin Wang, Hua Xie, Yiqing Lv, Yichen Huang, Yue Hong, Fang Chen

Background Urothelial regeneration is a crucial part of bladder tissue engineering. However, there is a lack of ideal “seed cells” in current practices. Here, we demonstrated that a sub-population of p63 positive basal cells could be activated and differentiate into intermediate and superficial umbrella cells after full-thickness mucosal resection in rabbit. Methods A focal mucosal resection model was used to characterize the role of different urothelial cells during regeneration. Urothelial basal cells were isolated from rabbit bladder mucosa and cultured in vitro. The basal cells were then transplanted in vivo in a manner of cell sheet for reconstruction. Results Via single-cell RNA sequencing (scRNA-seq), it has been confirmed that the cluster of KRT5high TP63-expressing cells possesses a ‘stemness’ signature which can give rise to lineage cell types sequentially. With a strong support from the underneath pre-set capsule vascular bed, the transplanted cell sheet could develop into a physio-morphology resembled to the native mucosa in vivo. Importantly, we validated that the bioengineered urothelium implemented perfect barrier function after implanted to bladder. Conclusions In summary, bioengineering urothelium with KRT5high TP63-expressing basal cells on a capsule vascular bed offers a promising strategy for bladder tissue engineering and provides a model for drug screening and bladder disease research.

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KRT5high TP63-expressing urothelial basal cells act as a driver to bladder urothelium regeneration in rabbit

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Original ResearchVol. 16, None • pp. 692DOI: 10.1186/s13287-025-04806-4

The human umbilical cord–mesenchymal stem cell secretome regulates hair growth and cycle transition by promoting methylthioadenosine synthesis via the PI3K/AKT/mTOR pathway

Authors: Yarui Zhang, Xueer Wang, Qimei Chen, Shan Zhao, Lingwei Bu, Shenhua Wu, Jianyuan Huang, Xunhong Xu, Xinyu Yang, Yong Miao, Lin Zhang, Min Zhang

Background The human umbilical cord (hUC)–mesenchymal stem cell (MSC) secretome (SCT) is a cell-free therapy that may emerge as a novel therapeutic strategy for hair loss prevention. Here, we aimed to elucidate the underlying mechanisms through which SCT regulates hair growth and cycle transition. Methods Using C57BL/6 mice, ex vivo follicles, and cell experiments, we studied the effects and mechanisms of SCT on hair growth and cycling using untargeted metabolomics and phosphoproteomics. A three-month double-blind clinical study was conducted to validate the effects of SCT on human hair. Results SCT promotes the telogen-to-anagen transition, hair thickening, and elongation of the vibrissae in mice; regulates dermal papilla cells and hair matrix cells through cysteine and methionine metabolism; and stimulates methylthioadenosine synthesis in hair matrix cells by activating the PI3K/AKT/mTOR signaling pathway. Clinical studies demonstrated that SCT increased human hair density and average hair diameter. Scalp physiological tests and subjective feedback indicated no related adverse reactions on the scalp or hair. Conclusions SCT promoted hair growth, thickening, and the hair follicle cycle via the PI3K/AKT/mTOR signaling pathway. This research provides a basis for the application of cell-free alternatives in hair care and hair loss prevention.

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The human umbilical cord–mesenchymal stem cell secretome regulates hair growth and cycle transition by promoting methylthioadenosine synthesis via the PI3K/AKT/mTOR pathway

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Original ResearchVol. 16, None • pp. 456DOI: 10.1186/s13287-025-04570-5

A systematic review of preclinical studies on therapeutic potential of mesenchymal stem/stromal cells and their secretome in bacterial infections

Authors: Leen Ali, Fatimah Shaaban, Elie Salem Sokhn, Fatima A. Saleh

Background Bacterial infections are a globally growing health issue, with an estimated 7.7 million deaths attributed to these infections worldwide. These life-threatening infections, primarily linked to antimicrobial resistance, are difficult to treat, and the growing reliance on last-resort antibiotics is exacerbating the problem. For this reason, numerous preclinical studies have been conducted using mesenchymal stem/stromal cells (MSCs) and their secretome as an alternative new therapeutic strategy for treating bacterial infections. However, these studies exhibit substantial disparities, often due to the lack of a consensus definition for MSCs and the broad variability in their reported characteristics. Thus, the purpose of this systematic review was to summarize studies that have used various sources of human MSCs and their secretome to treat bacterial infection in rodent models, to present an overview of evidence to proceed with clinical studies. Methods This systematic review was registered with PROSPERO and conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Using search terms related to “mesenchymal stem cells”, “mesenchymal stromal cells” as recommended by ISCT, “bacterial infections”, and “therapy”, candidate articles were identified through the PubMed database, and data were gathered using a narrative approach. Results Of the 517 articles retrieved, only thirty-seven studies met the inclusion criteria, and their analysis revealed several main findings. Human MSCs demonstrated positive effects mainly in decreasing bacterial load, reducing injuries, and improving the overall survival rate in rodents, with bone marrow-derived MSCs being the most used and effective type. All studies demonstrated that MSCs and their secretome can modify and enhance the immune response in rodents after bacterial infection. Conclusions This study showed that employing both stem cell-based and cell-free therapies for the treatment of bacterial infections has significant results in preclinical studies, offering promising potential as alternative treatment options. However, the findings are based solely on rodent models and the absence of donor-related investigations, necessitating further research to translate these findings into clinical applications.

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A systematic review of preclinical studies on therapeutic potential of mesenchymal stem/stromal cells and their secretome in bacterial infections

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Original ResearchVol. 16, NoneDOI: 10.1186/s13287-025-04260-2

Editorial Expression of Concern: Any closer to successful therapy of multiple myeloma? CAR-T cell is a good reason for optimism

Authors: Stem Cell Research & Therapy Editorial Board

The Editor-in-Chief of Stem Cell Research & Therapy is issuing an editorial expression of concern to alert readers that this article shows indication of irregularities in authorship during the publication process. The substantial authorship change that took place at revision does not appear to match the extent of the revision itself, and no sufficient rationale for the change has been provided by the authors. Navid Shomali, Roza Motavali did not state explicitly whether he agrees to this Expression of Concern. Faroogh Marofi, Safa Tahmasebi, Heshu Sulaiman Rahman, Max Stanley Chartrand, Rebar N. Mohammed, Yashwant Pathak and Roza Motavalli do not agree to this Expression of concern. Denis Kaigorodov, Alexander Markov, Alexei Valerievich Yumashev, Mostafa Jarahian and Farhad Motavalli Khiavi did not reply to correspondence from the Editor about this Expression of Concern.

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Editorial Expression of Concern: Any closer to successful therapy of multiple myeloma? CAR-T cell is a good reason for optimism

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Original ResearchVol. 16, None • pp. 235DOI: 10.1186/s13287-025-04366-7

Subchondral injection of human umbilical cord mesenchymal stem cells ameliorates knee osteoarthritis by inhibiting osteoblast apoptosis and TGF-beta activity

Authors: Congzi Wu, HuiHui Xu, Zhen Wu, Haipeng Huang, Qinwen Ge, Jianbo Xu, Jiali Chen, Pinger Wang, Wenhua Yuan, Hongting Jin, Peijian Tong

Background Osteoarthritis (OA) is a common degenerative disease caused by multiple pathological mechanisms wherein subchondral bone malfunction plays a substantial role. Recently, subchondral (SC) injection of orthobiologics has been attracting growing interest albeit the mainstream delivery method of mesenchymal stem cells (MSCs) is through intra-articular (IA). This study investigates the effect of SC injection of human umbilical cord mesenchymal stem cells (UCMSCs) on OA and its possible therapeutic mechanism compared to IA injection. Methods Male Sprague-Dawley rats with anterior cruciate ligament transection (ACLT) received saline or UCMSC injections via SC or IA. Consecutive injections once a week for three weeks and withdrawal for another four weeks, followed by Radiographical scanning, histopathological, immunohistochemical, and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labelling (TUNEL) staining. Cell counting Kit-8 (CCK-8) assay, alkaline phosphatase (ALP), alizarin red staining (ARS), TUNEL, flow cytometry, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were employed in TNFα-induced MC3T3-E1 cells to illustrate the exact pathogenesis mechanism. Results IA and SC UCMSC injections preserved cartilage, synovium, and subchondral bone parameters like trabecular bone volume fraction (BV/TV). SC injection uniquely improved Trabecular separation (Tb.Sp) and Trabecular number (Tb.N). SC and IA injections of UCMSCs demonstrated equivalent efficacy in promoting osteoblastic bone formation and attenuating aberrant angiogenesis of subchondral bone. In addition, we demonstrated that osteoblast apoptosis and Smad2-dependent TGF-beta (TGF-β) are crucial and interactive subchondral bone pathological features in OA. In vivo and vitro studies further revealed that UCMSCs inhibited excessive TGF-β/pSmad2 signaling to regulate osteoblast apoptosis and bone remodeling, thereby ameliorating OA progression. These findings suggest that SC injection of UCMSCs is a promising therapeutic strategy for OA, potentially offering advantages over IA injection in improving subchondral bone microarchitecture.

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Subchondral injection of human umbilical cord mesenchymal stem cells ameliorates knee osteoarthritis by inhibiting osteoblast apoptosis and TGF-beta activity

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Original ResearchVol. 16, None • pp. 439DOI: 10.1186/s13287-025-04560-7

Mechanisms and clinical progress of adipose-derived stem cells and their derivatives in the treatment of hair loss

Authors: Jiale Zhang, Feng Chen, Yue Hu, Xianling Cong

The rising prevalence of alopecia poses a significant challenge for both clinicians and researchers. As the global incidence of hair loss continues to increase, research into hair biology and regenerative mechanisms has gained considerable attention. However, current treatment options for alopecia are often constrained by limited efficacy and notable adverse effects. This underscores an urgent need for innovative therapeutic strategies to address these gaps. Adipose-derived stem cells (ADSCs), a subset of mesenchymal stem cells, represent a promising new approach in the treatment of alopecia. This review provides a detailed examination of the fundamental properties of ADSCs and their derivatives, exploring their mechanisms of action in alopecia therapy. Analysis of the efficacy of ADSCs and their derivatives in both preclinical and clinical settings highlight their potential to stimulate hair regeneration. Additionally, the review discusses various pre-treatment methods designed to enhance the regenerative capacity of ADSCs in hair growth, elucidating the mechanisms involved. The review also addresses the challenges and future directions for the use of ADSCs in alopecia treatment, aiming to offer valuable insights for both theoretical research and clinical practice. Ultimately, this work seeks to contribute to the development of more effective treatment regimens for alopecia.

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Mechanisms and clinical progress of adipose-derived stem cells and their derivatives in the treatment of hair loss

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Original ResearchVol. 16, None • pp. 616DOI: 10.1186/s13287-025-04751-2

CXCR5-engineered mesenchymal stromal cells home to spleen and mitigate post-sepsis syndrome by preventing secondary infection

Authors: Jiahao Shi, Lu Zhu, Xin Sui, Xiaomeng Yi, Xiaoyong Chen, Zhishan Li, Minjie Liu, Yingying Bao, Dongyan Zhu, Yuantao Li, Heshe Li, Ying Wang, Lin Nie, Rouchen Lin, Yunli Tong, Jing Huang, Jianqi Feng, Rui Fang, Tao Wang, Andy Peng Xiang, Xiaoran Zhang

Background Sepsis survivors frequently develop compromised humoral immunity, manifesting as prolonged immunosuppression that increases susceptibility to secondary infections with high associated mortality. While mesenchymal stromal cells (MSCs) have demonstrated efficacy in mitigating initial inflammatory responses and improving early survival rates in murine cecal ligation and puncture (CLP) models, they show limited effectiveness against subsequent secondary infections. Given that lymphopenia represents a primary driver of this infection vulnerability, we sought to investigate whether spleen-targeted MSC therapy could prevent lymphocyte depletion and enhance protection against secondary infections. Methods In this study, we developed CXCR5-overexpressing MSCs (MSCCXCR5) to enhance their targeted migration toward splenic CXCL13. Using a CLP mouse model followed by secondary Staphylococcus aureus (S. aureus) infection, we systematically evaluated the therapeutic potential of MSCCXCR5 in combating post-sepsis immunosuppression. Results MSCCXCR5 demonstrated enhanced splenic migration, specifically homing to CXCL13-rich B-cell zones, and conferred significant protection against both S. aureus secondary infection and sepsis-induced lymphopenia. Mechanistic investigations revealed that MSCCXCR5 treatment preserved follicular and germinal center B-cell populations, maintaining splenic architecture and potentiating antigen-specific B-cell responses to CLP challenge. These effects collectively contributed to markedly improved survival outcomes in CLP mice following secondary infection. Conclusion Our findings demonstrate that MSCCXCR5 confers dual-phase protection in sepsis, improving survival during both the initial hyperinflammatory phase and subsequent immunosuppressive period. This comprehensive

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CXCR5-engineered mesenchymal stromal cells home to spleen and mitigate post-sepsis syndrome by preventing secondary infection

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Original ResearchVol. 16, None • pp. 160DOI: 10.1186/s13287-025-04293-7

A perfect islet: reviewing recent protocol developments and proposing strategies for stem cell derived functional pancreatic islets

Authors: Sujitha Sali, Leen Azzam, Taraf Jaro, Ahmed Ali Gebril Ali, Ali Mardini, Omar Al-Dajani, Shahryar Khattak, Alexandra E. Butler, Juberiya M. Azeez, Manjula Nandakumar

The search for an effective cell replacement therapy for diabetes has driven the development of “perfect” pancreatic islets from human pluripotent stem cells (hPSCs). These hPSC-derived pancreatic islet-like β cells can overcome the limitations for disease modelling, drug development and transplantation therapies in diabetes. Nevertheless, challenges remain in generating fully functional and mature β cells from hPSCs. This review underscores the significant efforts made by researchers to optimize various differentiation protocols aimed at enhancing the efficiency and quality of hPSC-derived pancreatic islets and proposes methods for their improvement. By emulating the natural developmental processes of pancreatic embryogenesis, specific growth factors, signaling molecules and culture conditions are employed to guide hPSCs towards the formation of mature β cells capable of secreting insulin in response to glucose. However, the efficiency of these protocols varies greatly among different human embryonic stem cell (hESC) and induced pluripotent stem cell (hiPSC) lines. This variability poses a particular challenge for generating patient-specific β cells. Despite recent advancements, the ultimate goal remains to develop a highly efficient directed differentiation protocol that is applicable across all genetic backgrounds of hPSCs. Although progress has been made, further research is required to optimize the protocols and characterization methods that could ensure the safety and efficacy of hPSC-derived pancreatic islets before they can be utilized in clinical settings.

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A perfect islet: reviewing recent protocol developments and proposing strategies for stem cell derived functional pancreatic islets

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Original ResearchVol. 16, NoneDOI: 10.1186/s13287-025-04214-8

Correction: Adenovirus-mediated transfer of hepatocyte growth factor gene to human dental pulp stem cells under good manufacturing practice improves their potential for periodontal regeneration in swine

Authors: Yu Cao, Zhenhai Liu, Yilin Xie, Jingchao Hu, Hua Wang, Zhipeng Fan, Chunmei Zhang, Jingsong Wang, Chu-Tse Wu, Songlin Wang

The authors wish to note the following correction: The images in Fig. 2D of our paper, which were intended to show Annexin V staining for apoptosis of human dental pulp stem cells (hDPSCs) and HGF-transfected hDPSCs (HGF-hDPSCs) under hypoxic conditions or serum-free media, were incorrect. The original results demonstrated that more apoptotic cells were observed in the hDPSCs group compared to the HGF-hDPSCs group. However, we inadvertently used images of Annexin V staining for apoptosis in human bone marrow mesenchymal stem cells (hBMSCs) and HGF-transfected hBMSCs (HGF-hBMSCs). Upon reviewing the original experimental records, we discovered that the incorrect images were included during the manuscript preparation process due to insufficient verification. We have now provided the correct images for hDPSCs and HGF-hDPSCs in Fig. 2D (see attachment). We sincerely apologize for this oversight. This error occurred because our research group has been extensively engaged in studying the biological characteristics of HGF gene-transfected mesenchymal stem cells. Unfortunately, due to carelessness, we mistakenly selected the wrong images. Nevertheless, our research consistently demonstrates that the anti-apoptotic ability of mesenchymal stem cells (including rBMSCs, hBMSCs, and hDPSCs) is enhanced under hypoxic conditions or serum-free media following HGF gene transfection. The methodology and results remain consistent with our previous studies. After thoroughly reviewing all data and experimental records, we confirm that this correction does not affect the validity of the original study’s results or conclusions.

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Correction: Adenovirus-mediated transfer of hepatocyte growth factor gene to human dental pulp stem cells under good manufacturing practice improves their potential for periodontal regeneration in swine

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Original ResearchVol. 16, Issue 1 • pp. 493DOI: 10.1186/s13287-025-04577-y

Allogeneic bone marrow-derived mesenchymal stem cells in the aging kidney: secondary results of a Parkinson's disease clinical trial

Authors: Juan D. Martinez-Lemus, Donald A. Molony, Jessika Suescun, Emily Tharp, Tia S. Thomas, Charles Green, Chiamaka Onuigbo, Robert Ritter III, Mya C. Schiess

Background Kidney function declines with age, largely due to chronic low-grade inflammation. Mesenchymal stem cells (MSCs) have demonstrated immunomodulatory effects in certain immune-mediated kidney diseases, but their role in preserving renal function in aging individuals without chronic kidney disease (CKD) remains unclear. This study presents secondary outcome findings from a randomized clinical trial in Parkinson's disease (PD), evaluating the impact of allogeneic human bone marrow-derived MSCs (allo-hMSCs) on kidney function in an aging population with PD with preserved renal function. Methods Subjects with PD aged 50–79 years with baseline estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2 were randomized to receive either three allo-hMSC infusions, one placebo followed by two allo-hMSC infusions, or three placebo infusions at 18-week intervals. Kidney function was assessed using eGFR, serum creatinine (SCr), and blood urea nitrogen (BUN) at baseline, 9 weeks after the first two infusions, and at weeks 40 and 88. eGFR was calculated using the 2021 CKD-EPI equation. A Bayesian modeling approach was used to estimate posterior probabilities (PP) of treatment effects. Results Of 45 randomized patients, 44 were analyzed; 43 completed infusions, and 40 completed the 88-week follow-up. The three-infusion group (N=16) showed an average annual eGFR increase of 3.29 mL/min/1.73 m2, versus declines of –1.46 and –2.92 in the two-infusion (N=14) and placebo (N=15) groups. SCr decreased by –0.12 mg/dL at both weeks 40 (PP: 93.9%) and 88 (PP: 86.2%) in the three-infusion group versus placebo, with no significant SCr differences between the two-infusion and placebo groups. BUN levels did not differ significantly between treatment and placebo groups. Conclusion In older adults with PD and preserved kidney function, repeated allo-hMSC infusions were associated with improved kidney function measures. While promising, these findings are preliminary and may be specific to PD. Further studies are needed to assess potential benefits in the broader aging population. Trial Registration ClinicalTrials.Gov. NCT04506073. November 09, 2020. https://clinicaltrials.gov/study/NCT04506073

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Allogeneic bone marrow-derived mesenchymal stem cells in the aging kidney: secondary results of a Parkinson's disease clinical trial

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Original ResearchVol. 16, None • pp. 607DOI: 10.1186/s13287-025-04727-2

SPARC-modified mesenchymal stem cells promote recovery of β-cells and insulin secretion by calcium ion homeostasis

Authors: Jiaqi Gao, Balun Li, Hongkai Tian, Chenchen Li, Nikita Merzlikin, Dongyao Han, Zixi Ling, Zengyu Zhang, Wenlong Zhu, Jianqi Dai, Lydmila Gerunova, Changrong Lv, Na Li, Jinlian Hua

Introduction Type 1 diabetes (T1D) results from the destruction of pancreatic β-cells, leading to insulin deficiency. As insulin therapy does not affect disease progression, advancements in immune regulation therapies have emerged, including the reconstitution of the insulin secretory system. Cysteine-rich acidic secretory protein (SPARC) is an extracellular matrix glycoprotein that regulates cell adhesion, facilitating cell migration, and mediating interactions between cells and their extracellular matrix. SPARC is overexpressed during tissue repair and is involved in β-cells survival. However, the potential of SPARC-modified mesenchymal stem cells (MSCs) to improve insulin secretion has not been thoroughly investigated. This study investigated the therapeutic effects of SPARC-MSCs in vivo and in vitro and assessed whether SPARC enhances survival and insulin secretion after β-cells injury. Methods In vivo, we established T1D models in mice and canine using SPARC-MSCs for cell transplantation. In vitro, MIN6 cells were damaged with STZ, and SPARC-MSC supernatant was co-cultured with MIN6 for various assays. Results Our study demonstrated that SPARC enhanced the regenerative capacity and migratory efficiency of MSCs after H2O2 injury and improved their morphology. In STZ-induced canine and mice diabetes models, SPARC-MSCs therapy significantly reduced hyperglycemia, improved oral glucose tolerance test (OGTT), and reversed weight loss in canine. Biochemical analyses showed improved liver function, and histological examination revealed restored islet area was significantly restored. Transcriptome and proteome sequencing indicated significant enrichment in calcium binding and cell migration pathways. Co-culturing SPARC-MSC supernatant with MIN6 cells after STZ injury restored their regenerative ability, enhancing insulin secretion and ATP content under high glucose stimulation. SPARC treatment also significantly increased intracellular Ca2+ levels in MIN6 cells. Conclusion SPARC significantly promotes cell regeneration and stimulates insulin secretion by increasing intracellular ATP and Ca2+ influx. In diabetic canine and mice models, it alleviated hyperglycemia, improved glucose tolerance, and enhanced pancreatic islet area and insulin secretion.

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SPARC-modified mesenchymal stem cells promote recovery of β-cells and insulin secretion by calcium ion homeostasis

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Original ResearchVol. 16, None • pp. 365DOI: 10.1186/s13287-025-04475-3

Human adipose-derived stem cell exosomes reduce mitochondrial DNA common deletion through PINK1/Parkin-mediated mitophagy to improve skin photoaging

Authors: Yihao Wang, Wanxing Liao, Yiping Wang, Junlin Liao, Nian Chen, Chiyu Jia, Li Zeng

Background: Mitochondrial DNA (mtDNA) deletion and oxidative stress are key contributors to skin photoaging. Mitophagy helps mitigate oxidative stress. Human adipose-derived stem cell exosomes (hADSC-Exos) have been shown to counteract skin photoaging. This study aimed to explore the role and mechanism of hADSC-Exos in addressing skin photoaging. Methods: hADSC-Exos were isolated, and their surface markers were identified. Human dermal fibroblasts (HDFs) and nude mice were exposed to ultraviolet-B (UVB) irradiation, and treated with hADSC-Exos. Oxidative stress and photoaging were assessed through SA-β-gal staining, p21 expression, mtDNA deletion, reactive oxygen species (ROS) levels, and histological analysis. The PINK1, Parkin, LC3b, and p62 protein levels were measured to evaluate mitophagy. The PINK1 small-interfering RNA (siPINK1) was then used in HDFs to investigate the role of hADSC-Exos in mitophagy. Results: In UVB-exposed HDFs and nude mice, the number of SA-β-gal-positive cells, along with levels of p21, ROS, and mtDNA deletion, were significantly increased, but these effects were reduced by hADSC-Exos. Moreover, hADSC-Exos treatment significantly elevated PINK1 and Parkin levels, as well as the LC3bII/I ratio, while reducing p62 expression. In photoaged HDFs treated with hADSC-Exos, PINK1 knockout using siRNA decreased the LC3bII/I ratio and levels of PINK1 and Parkin, while increasing p62, ROS, and mtDNA deletion compared to the negative control (NC) group. Conclusion: hADSC-Exos can mitigate skin photoaging by promoting PINK1/Parkin-mediated mitophagy, thereby reducing mtDNA deletion and oxidative stress.

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Human adipose-derived stem cell exosomes reduce mitochondrial DNA common deletion through PINK1/Parkin-mediated mitophagy to improve skin photoaging

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Original ResearchVol. 16, None • pp. 518DOI: 10.1186/s13287-025-04635-5

Hyaluronic acid–ornithine crosslinked hydrogel as a superior 3D culture platform for high-quality exosome production in advanced wound healing

Authors: Shuangquan Qu, Rui Zhao, Ke Li, Yutao Tan, Pei Li, Biwu Liu, Jieru Yang, Wenhu Zhou

Background: Extracellular vesicle (EV)-based cell-free therapies have emerged as a powerful alternative to stem cell transplantation in regenerative medicine, owing to their ability to promote tissue repair while avoiding safety concerns associated with live-cell therapies. However, traditional two-dimensional (2D) cell cultures used for EV production are constrained by low exosome (Exo) yields and limited biological activity. Objective: This study introduces a novel and scalable three-dimensional (3D) culture platform based on a hyaluronic acid (HA) and L-ornithine methyl ester (Orn) hydrogel to enhance the production and therapeutic efficacy of stem cell-derived exosomes. Methods: The HA-Orn hydrogel was fabricated via a simple and mild crosslinking strategy, forming a biomimetic matrix that promotes spontaneous spheroid formation. Exosomes derived from 3D cultures (3D-Exo) were compared with those from 2D cultures (2D-Exo) in terms of yield, molecular composition, and biological functions. Results: 3D-Exo exhibited significantly increased yield and superior functional properties, including enhanced stimulation of cell proliferation, migration, angiogenesis, and extracellular matrix remodeling. In vivo, 3D-Exo treatment accelerated wound closure and reduced inflammation in a mouse skin injury model, demonstrating robust therapeutic efficacy and safety. Mechanistic studies revealed distinct miRNA expression profiles and activation of regenerative signaling pathways in 3D-Exo. Conclusion: This work presents a cost-effective, scalable, and bioinspired 3D culture system for high-yield and functionally enhanced Exo production. The HA-Orn hydrogel platform offers significant translational potential for advancing cell-free regenerative therapies, particularly in the context of wound healing.

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Hyaluronic acid–ornithine crosslinked hydrogel as a superior 3D culture platform for high-quality exosome production in advanced wound healing

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Original ResearchVol. 16, Issue 150 • pp. 1-16DOI: 10.1186/s13287-025-04264-y

From gut to liver: organoids as platforms for next-generation toxicology assessment vehicles for xenobiotics

Authors: Sulaiman Mohammed Alnasser

Traditional toxicological assessment relied heavily on 2D cell cultures and animal models of study, which were inadequate for the precise prediction of human response to chemicals. Researchers have now shifted focus on organoids for toxicological assessment. Organoids are 3D structures produced from stem cells that mimic the shape and functionality of human organs and have a number of advantages compared to traditional models of study. They have the capacity to replicate the intricate cellular microenvironment and in vivo interactions. They offer a physiologically pertinent platform that is useful for the researchers to monitor cellular responses in a more realistic manner and evaluate drug toxicity. Additionally, organoids can be created from cells unique to a patient, allowing for individualized toxicological research and providing understanding of the inter-individual heterogeneity in drug responses. Recent developments in the use of gut and liver organoids for assessment of the xenobiotics (environmental toxins and drugs) is reviewed in this article. Gut organoids can reveal potential damage to the digestive system and how xenobiotics affect nutrient absorption and barrier function. Liver is the primary site of detoxification and metabolism of xenobiotics, usually routed from the gut. Hence, these are linked and crucial for evaluating chemical or pollutant induced organ toxicity, forecasting their metabolism and pharmacokinetics. When incorporated into the drug development process, organoid models have the potential to improve the accuracy and efficiency of drug safety assessments, leading to safer and more effective treatments. We also discuss the limitations of using organoid-based toxicological assays, and future prospects, including the need for standardized protocols for overcoming reproducibility issues.

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From gut to liver: organoids as platforms for next-generation toxicology assessment vehicles for xenobiotics

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Original ResearchVol. 16, None • pp. 666DOI: 10.1186/s13287-025-04788-3

Mesenchymal stem cell therapy for end-stage liver disease: adversity and opportunity

Authors: Shiqi Li, Yichen Wang, Su-meng Li, Yaxin Zhu, Yan-qin Du, Xin Zheng, Jun Wu

End-stage liver disease (ESLD) is one of the predominant diseases contributing to high morbidity and mortality worldwide, with etiologies including alcoholic liver disease, viral hepatitis, non-alcoholic fatty liver disease, and metabolic-associated liver disease. Currently, liver transplantation remains the only effective treatment, however, its clinical application is significantly limited by donor shortages, immune rejection, and high medical costs. Among the five types of stem cells that have been experimentally applied to liver diseases, mesenchymal stem cells (MSCs) have emerged as the most extensively studied, with the largest number of experimental and clinical research platforms worldwide. This review compiles findings from 25 preclinical and clinical studies on MSCs in the treatment of ESLD, aiming to elucidate the core mechanisms of action and then outline both the challenges in MSC clinical translation and the novel opportunities arising from cutting-edge research.

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Mesenchymal stem cell therapy for end-stage liver disease: adversity and opportunity

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Original ResearchVol. 16, None • pp. 205DOI: 10.1186/s13287-025-04329-y

Human platelet lysate produced from leukoreduction filter contents enables sufficient MSC growth

Authors: Shinobu Wakamoto, Tomoko Furukawa, Masahito Kawabori, Mitsuaki Akino, Shiho Kato, Hisae Fuse, Sumio Ohtsuki, Yoshihiro Torimoto, Miki Fujimura, Shuichi Kino

Background Stem cell therapy holds significant potential for promoting recovery, with numerous products currently under development. Blood-derived supplements are often essential for successful stem cell expansion, with fetal bovine serum (FBS) being the most commonly used supplement. However, FBS has drawbacks, including the risk of immune responses, ethical concerns about animal welfare, and potential zoonotic infections. Human platelet lysate (hPL), derived from lysed platelets, contains various growth factors and has been proposed as an alternative to FBS. However, obtaining sufficient human platelets for clinical use remains challenging. Leukoreduction filters, used during blood transfusion manufacturing to remove leukocytes, also retain significant amounts of platelets and plasma. This study investigates the feasibility and efficacy of filter-derived hPL (f-hPL) for mesenchymal stem cell (MSC) expansion. Methods Leukoreduction filters were collected after their use in the manufacturing of whole blood transfusion products. Each filter was reverse-perfused with saline to extract residual blood contents. Platelets (f-platelet) and supernatant were separated by multiple centrifugation steps. f-Platelet were lysed with varying concentrations of fresh frozen plasma (FFP) to determine the optimal protein concentration for the lysate solution. Then, plasma left in the leukoreduction filters were used to generate lysate solution (f-plasma) at optimal protein concentration. f-Platelet (1.1 × 10^9/mL) and f-plasma (27 mg/mL protein) were combined in a freezing bag and subjected to three freeze-thaw cycles to produce f-hPL. Both small- and large-scale f-hPL were manufactured, and MSCs expansion and quality assessments were perfomed to evaluate the efficacy of f-hPL. Results A total of 3.5 ± 0.6 × 10^10 f-platelets were obtained from a single leukoreduction filter, yielding a collection efficiency of 37.1 ± 5.3%. The optimal protein concentration of lysate solution for cell expansion was > 27 mg/mL. Subsequently, six leukoreduction filters used to produce enough f-platelet and p-plasma for 100 mL of f-hPL. MSCs cultured in medium supplemented with 10% f-hPL demonstrated superior expansion, with cell proliferation rates 20% higher than those observed with commercial hPL and 300% higher than those cultured with FBS. The expanded MSCs met the International Society for Cell & Gene Therapy criteria for cell surface markers and differentiation potential.

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Human platelet lysate produced from leukoreduction filter contents enables sufficient MSC growth

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Original ResearchVol. 16, None • pp. 497DOI: 10.1186/s13287-025-04629-3

Fucoxanthin protects placenta-derived human mesenchymal stem cells against oxidative stress-induced apoptosis by modulating genes involved in DNA damage repair, ER stress response, p53-induced apoptosis

Authors: Gunticha Suwanmanee, Pakpoom Kheolamai, Chairat Tantrawatpan, Daniel Grimes, Ioan Valentin Matei, Luminita Paraoan, Sirikul Manochantr

Human mesenchymal stem cells (hMSCs) hold significant promise in regenerative medicine due to their ability to reduce inflammation and promote tissue repair. However, their therapeutic potential is often compromised by their high susceptibility to apoptosis under oxidative stress, prevalent in the microenvironment of the target tissues. Our previous study showed that fucoxanthin, a carotenoid derived from brown algae, can improve the viability of placenta-derived mesenchymal stem cells (PL-MSCs) by reducing intracellular ROS levels through the activation of the PI3K/Akt/Nrf-2 signaling pathway. In this study, we further investigate the mechanisms underlying the protective effect of fucoxanthin against oxidative stress-induced apoptosis in PL-MSCs, using an in vitro model. PL-MSCs were cultured with 750 µM H2O2 to induce oxidative stress and treated with various concentrations of fucoxanthin for 48 h. The effect of fucoxanthin on PL-MSC apoptosis under oxidative stress conditions was determined using CCK-8, Annexin V/DRAQ7™ apoptosis assays, as well as the expression of apoptosis-related genes and proteins. The effect of fucoxanthin on the transcriptome of PL-MSCs under oxidative stress conditions was also assessed by high-throughput Nanostring analysis. The results showed that fucoxanthin significantly decreased the apoptosis of PL-MSCs under oxidative stress in a dose-dependent manner by reducing the expression of pro-apoptotic proteins and inhibiting their activation, while increasing the expression of anti-apoptotic proteins in these cells. Furthermore, fucoxanthin also downregulates the expression of genes associated with the endoplasmic reticulum stress, p53-induced apoptosis, while increasing the expression of genes involved in the regulation of the cell cycle, DNA damage repair, cytokine signaling, nucleotide synthesis, PI3K/mTOR pathway and AMPK pathway in PL-MSCs under oxidative stress conditions. Taken together, the findings provide compelling evidence that fucoxanthin protects PL-MSCs against oxidative stress-induced apoptosis by modulating the expression of various genes involved in DNA damage repair, ER stress response, p53-induced apoptosis in these cells. This suggests that fucoxanthin could be used as a potential supplement to enhance the therapeutic efficacy of MSC-based therapies.

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Fucoxanthin protects placenta-derived human mesenchymal stem cells against oxidative stress-induced apoptosis by modulating genes involved in DNA damage repair, ER stress response, p53-induced apoptosis

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Original ResearchVol. 16, None • pp. 644DOI: 10.1186/s13287-025-04764-x

Morphometric prediction of mesenchymal stromal cell-like immunosuppressive capacity of human hair follicle dermal sheath cup cells: an implication for regenerative medicine in hair loss diseases

Authors: Hyuma Tsuji, Hsing-Yi Lin, Suguru Kinoshita, Hidemasa Jinguji, Yosuke Nakazawa, Masashi Ogo, Manabu Ohyama

Background Human hair follicle dermal sheath cup cells (DSCCs) hold promise as a cell source of regenerative medicine treatment for hair loss owing to their ability to secrete growth factors and/or signal pathway activators. The therapeutic effect of autologous DSCCs transplantation for male/female pattern hair loss (PHL) was demonstrated in a phase III equivalent clinical study. Intralesional inflammation has been implicated in the pathophysiology of various hair loss diseases, including PHL. As DSCCs possess mesenchymal stem/stromal cell (MSC)-like properties and MSCs are immunosuppressive, we investigated whether they exhibit immunoregulatory capabilities comparable to MSCs and developed an in vitro morphometric assay to predict this capability. Methods DSCCs were isolated via microdissection and propagated in vitro. Their conformity to MSC criteria was assessed based on cell surface antigen expression and differentiation potential. Furthermore, immunoregulatory capabilities were assessed by co-culturing DSCCs with anti-CD3/28 antibody-stimulated peripheral blood mononuclear cells (PBMCs) and examining the suppression mechanisms through pharmacological intervention. Multiple lots of DSCCs derived from various donors and manufacturing conditions were cultured and analyzed by phase-contrast microscopy to obtain their morphometric profiles. Parameters correlating with the expression levels of immunomodulatory factors were used to create a predictive model. Additional DSCC lots were manufactured to validate the predictive model. Results Similar to MSCs, cell differentiation assays revealed that DSCCs exhibited multipotency, and they did not express co-stimulatory molecules in response to immunogenic stimuli, suggesting low immunogenicity. Moreover, co-culture experiments with allogeneic PBMCs revealed that DSCCs reduced T cell proliferation (from 78 to 5%) and

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Morphometric prediction of mesenchymal stromal cell-like immunosuppressive capacity of human hair follicle dermal sheath cup cells: an implication for regenerative medicine in hair loss diseases

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Original ResearchVol. 16, None • pp. 391DOI: 10.1186/s13287-025-04527-8

CD317 stabilizes TNFR1 and confers the anti-inflammatory functions of MSCs via NF-κB/TSG6 pathway

Authors: Si Chen, Lan Yao, Xin Wen, Xianqi Wang, Lin Chen, Jingting Zhang, Jianyong Xu

Background Although both pre-clinical and clinical studies show promising outcomes, resulting in rapid growth of clinical trials of MSC-based therapies in recent years, the heterogeneity and therapeutic inconsistency of MSCs have severely hampered their clinical applications. Purifying homogenous MSC populations with enhanced specific functions represents one promising approach. We have demonstrated recently that the CD317+ MSCs have enhanced anti-inflammatory functions and improved therapeutic efficacy and consistency. Methods In the current study, we performed both in vitro and in vivo investigations to delineate whether and how CD317 regulates the immune modulation function of MSCs. Results Our data here indicate that the CD317 directly contributes to the immune suppression function of MSCs stimulated by TNF-α through up-regulating TSG6 via CD317/lipid-raft/TNFR1 complex. The CD317 stabilizes the TNFR1 complex, resulting in hyper-activation of the NF-κB pathway and up-regulation of TSG6, which confers the therapeutic effects of MSCs on the mouse model of ALI (acute lung injury) and IBD (inflammatory bowel disease). Conclusions Thus, the CD317 stabilizes TNFR1 and confers the anti-inflammatory functions of MSCs via NF-κB/TSG6 Pathway.

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CD317 stabilizes TNFR1 and confers the anti-inflammatory functions of MSCs via NF-κB/TSG6 pathway

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Original ResearchVol. 16, None • pp. 265DOI: 10.1186/s13287-025-04360-z

Clinical application of mesenchymal stem cells in immunosenescence: a qualitative review of their potential and challenges

Authors: Xu Wang, Dan Guo, Chengmei He, Xiaoxi Wang, Yi Wei, Fengchun Zhang, Li Wang, Yanlei Yang

Aging leads to a gradual decline in immune function, termed immunosenescence, which significantly elevates the susceptibility to infections, cancers, and other aging-related diseases. Recent advancements have shed light on the molecular underpinnings of immune aging and pioneered novel therapeutic interventions to counteract its effects. Mesenchymal stem cells (MSCs)-a type of multipotent stromal cells with regenerative potential, low immunogenicity, and strong immunomodulatory properties-are increasingly recognized as a promising therapeutic option to reverse or alleviate immunosenescence-related dysfunction. This review systematically summarizes recent discoveries on how MSCs counteract immune aging, particularly their ability to rejuvenate aged immune cells and restore immune homeostasis. It also addresses key challenges, such as variations in MSC sources, donor variability, and the lack of standardized protocols, while proposing future directions to enhance therapeutic precision. Although preclinical and clinical studies highlight the potential of MSC-based strategies for delaying immunosenescence, critical issues remain unresolved, including long-term safety and efficacy, optimizing cell delivery systems, and elucidating context-specific mechanisms. Addressing these challenges will accelerate the development of MSC-based therapies to combat aging-associated immune decline.

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Clinical application of mesenchymal stem cells in immunosenescence: a qualitative review of their potential and challenges

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Original ResearchVol. 16, None • pp. 502DOI: 10.1186/s13287-025-04660-4

Three-dimensional midbrain organoids: a next-generation tool for Parkinson's disease modelling and drug discovery

Authors: Rosalie Elvira, Eng King Tan, Zhi Dong Zhou

Parkinson's disease (PD), a progressive neurodegenerative disorder marked by dopaminergic (DA) neuron loss and Lewy body formation, lacks therapies to halt neurodegeneration. Current models, including 2D cultures and animal studies, fail to fully recapitulate human midbrain complexity, underscoring the need for advanced human-relevant disease modelling systems. Midbrain organoids (MOs), three-dimensional (3D) stem cell-derived neuronal structures mimicking midbrain architecture, have emerged as transformative tools for modelling PD. These organoids replicate key pathological hallmarks and enable disease mechanistic studies and drug screening for PD. Recent advances of research in MOs include genetic modelling of PD-linked mutations (e.g., LRRK2, GBA1, DNAJC6), optogenetics-assisted α-synuclein (α-syn) protein aggregation systems, and high-throughput drug testing platforms. MOs also show promise for cell replacement therapy, with successful integration and functional recovery in animal PD models. However, challenges such as batch variability, limited vascularization, incomplete neuronal maturation, and high costs hinder reproducibility and scalability. Future directions focus on integrating vascular networks, microglia co-cultures, automated workflows, and assembloid technologies to enhance pathophysiological relevance and translational potential in PD. By addressing these limitations, research in MOs could revolutionize PD research, offering critical insights into disease mechanisms and accelerating therapeutic discovery for PD patients.

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Three-dimensional midbrain organoids: a next-generation tool for Parkinson's disease modelling and drug discovery

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Original ResearchVol. 16, None • pp. 599DOI: 10.1186/s13287-025-04718-3

L-Glutamate enables the EGFR-MEK-ERK-mTFB2 axis to enhance mitochondrial biogenesis in intestinal stem cells

Authors: Cai-xia Dou, Hao-zhan Qu, Ying-chao Qin, Xiao-fan Wang, Jia-yi Zhou, Xiu-qi Wang, Hui-chao Yan

Background Intestinal stem cells (ISCs) sustain epithelial homeostasis through rapid mitochondrial metabolism, however, how they sense nutrient signals to regulate mitochondrial function remains unclear. Methods We examined the role of L-glutamate (Glu) in regulating cell mitochondrial biosynthesis using in vivo piglets, ex vivo porcine intestinal organoids (IOs), and in vitro IPEC-J2 cells. Results Glu enhanced jejunal development in weaned piglets. Isobaric tags for relative and absolute quantitation (iTRAQ) analysis revealed the significant enrichment of mitochondrial functions and activation of EGFR-MEK-ERK-mTFB2 signaling pathway in the jejunum. In vitro, 5 mM Glu promotes mitochondrial biosynthesis and potentiates the EGFR-MEK-ERK-mTFB2 axis. Whereas inhibition of EGFR with Osimertinib and silencing EGFR abolished these effects in IOs and IPEC-J2 cells. Colocalization and biochemical studies demonstrated interaction between Glu and EGFR in IOs. Conclusions Glu promotes mitochondrial biogenesis and ISC expansion by activating the EGFR–MEK–ERK–mTFB2 axis, highlighting a nutrient-sensing mechanism that couples energy availability to ISC function.

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L-Glutamate enables the EGFR-MEK-ERK-mTFB2 axis to enhance mitochondrial biogenesis in intestinal stem cells

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Original ResearchVol. 16, None • pp. 380DOI: 10.1186/s13287-025-04525-w

Overexpression of SOX4 in MSCs inhibits cellular senescence and enhances therapeutic efficacy in systemic lupus erythematosus

Authors: Jingjing Qi, Xiangge Zhao, Xiaoyu Gao, Xiaolu Zhu, Junli Wang, Jiaqing Liu, Jing Wei, Xia Li, Bihu Gao

Background Mesenchymal stem cells (MSCs) are widely used in treating autoimmune diseases. However, replicative senescence limits the quantity and quality of MSCs during population doublings in vitro. Transcription factor SOX4 is a crucial regulator of cell fate and stemness. This study aims to explore the role of SOX4 in senescence of MSCs and enhance their therapeutic efficacy in systemic lupus erythematosus (SLE). Methods In early-passage MSCs (P3), late-passage MSCs (P8), SOX4 downregulated P3-MSCs or SOX4 overexpressed P8-MSCs, cell morphology, mitochondrial reactive oxygen species (mtROS), senescence-associated β-galactosidase (SA-β-Gal) activity, cell proliferation rate, senescence-associated secretory phenotype (SASP) factors, cell cycle suppressors, the immunosuppressive effects on T cell activation and proliferation and the expression levels of SOX4 were determined. Imiquimod induced SLE mice were transplanted with P3-MSCs and P8-MSCs or control and SOX4 overexpressed P8-MSCs, and clinical symptoms were assessed. Results Compared to P3-MSCs, P8-MSCs display a senescent phenotype, increased mtROS, SA-β-Gal activity, SASP factors, and cell cycle suppressors p53, p21, and p16. Additionally, P8-MSCs have a reduced immunosuppressive function on T cell activation and proliferation, and express lower levels of SOX4. Downregulation of SOX4 in P3-MSCs promotes cellular senescence and impairs their immunosuppressive function. Conversely, overexpression of SOX4 in P8-MSCs ameliorates cellular senescence and enhances their immunosuppressive function. Furthermore, transplantation of P3-MSCs or SOX4-overexpressing P8-MSCs demonstrates greater therapeutic significantly efficacy in SLE mice compared to P8-MSCs.

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Overexpression of SOX4 in MSCs inhibits cellular senescence and enhances therapeutic efficacy in systemic lupus erythematosus

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Original ResearchVol. 16, None • pp. 93DOI: 10.1186/s13287-025-04241-5

aFGF gene-modified adipose-derived mesenchymal stem cells promote healing of full-thickness skin defects in diabetic rats

Authors: Yiren Zhu, Pinhua Chen, Zhengchao Zhang, XueYi He, Ruoli Wang, Qi Fang, Zhixian Xu, Wubing He

Background Chronic diabetic wounds pose a significant clinical challenge due to the limited efficacy of current treatments. This study aimed to investigate the role and potential mechanisms of adipose-derived mesenchymal stem cells (ADSCs) overexpressing acidic fibroblast growth factor (aFGF) in diabetic wound healing in a rat model. Methods ADSCs were genetically modified to achieve stable overexpression of aFGF. Varying doses of aFGF-ADSCs (1×10⁶, 2×10⁶, 3×10⁶, 4×10⁶) were injected into the muscular tissue surrounding diabetic rat wounds. We assessed aFGF expression and its impact on various stages of wound healing, including angiogenesis, inflammatory response, epithelialization, and collagen deposition. Transcriptomic sequencing was performed to explore the underlying mechanisms driving enhanced wound healing. Results Lentiviral transduction successfully induced stable aFGF overexpression in ADSCs. In vivo experiments revealed that varying doses of aFGF-ADSCs markedly enhanced wound healing in diabetic rats in a dose-dependent manner. The dose of 3×10⁶ aFGF-ADSCs demonstrated the most significant effect. In the 3×10⁶ aFGF-ADSCs group, expression levels of aFGF, CD31, and CD163 were significantly higher than in other groups (p < 0.05), while CD86 expression was significantly lower (p < 0.05). Conclusion Single doses of aFGF-ADSCs comprehensively improved various aspects of wound repair in diabetic rats, offering a potential new approach for treating chronic diabetic wounds. The mechanism of action involves promoting angiogenesis, modulating inflammatory responses, accelerating epithelialization, and optimizing collagen deposition.

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aFGF gene-modified adipose-derived mesenchymal stem cells promote healing of full-thickness skin defects in diabetic rats

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Original ResearchVol. 16, Issue 1 • pp. 14DOI: 10.1186/s13287-025-04131-w

Bone marrow mesenchymal stem cells derived cytokines associated with AKT/IAPs signaling ameliorate Alzheimer’s disease development

Authors: Yalan Lu, Yanfeng Xu, Li Zhou, Siyuan Wang, Yunlin Han, Kewei Wang, Chuan Qin

Background Alzheimer’s disease (AD) is a progressive neurodegenerative condition affecting around 50 million people worldwide. Bone marrow-derived mesenchymal stem cells (BMMSCs) have emerged as a promising source for cellular therapy due to their ability to differentiate into multiple cell types and their paracrine effects. However, the direct injection of BMMSCs can lead to potential unpredictable impairments, prompting a renewed interest in their paracrine effects for AD treatment. The specific mechanism and central role of cytokines in this process have not been fully elucidated. Methods Mouse BMMSCs were isolated, validated, and then transplanted intracerebrally into APP/PS1 female mice. The behavioral tests, including open-field test, novel object recognition test, and Morris water maze were performed, followed by β-amyloidosis plaque and neuron apoptosis analyses. Then the tissue RNA sequencing and mBMMSC cytokine analysis were performed. A cytokine antibody array for BMMSCs and the brain slice models were performed with AD model tissues were used to elucidate the molecular mechanisms. Finally, APP/PS1 mice were administrated with cytokine mixture for cognitive recovery. Results Our results demonstrated that BMMSCs significantly improved cognitive function, reduced beta-amyloid plaque deposition, and decreased apoptotic neurons through the activation of the AKT signaling pathway. Using a cytokine antibody array, we identified three highly expressed AKT pathway regulated neuroprotective factors in BMMSCs: IGF1, VEGF, and Periostin2. These cytokines were found to upregulate inhibitors of apoptosis family proteins (IAPs) and suppress Caspase-3 activity in brain slices induced with beta amyloidosis (Aβ), okadaic acid (OA), and lipopolysaccharide (LPS). When injection of this cytokine mixture to APP/PS1 mice also resulted in a mitigation of cognitive impairment. Conclusions These findings suggest that the secretory factors IGF1, VEGF, and Periostin2 derived from BMMSCs play a crucial role in neuroprotection by modulating the AKT/IAPs pathway to restore neuronal function. These cytokine sets could be a potential therapeutic strategy for AD and lay the groundwork for promising clinical applications.

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Bone marrow mesenchymal stem cells derived cytokines associated with AKT/IAPs signaling ameliorate Alzheimer’s disease development

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Original ResearchVol. 16, None • pp. 346DOI: 10.1186/s13287-025-04428-w

MSCs engineered with secreted Klotho alleviate blood–brain barrier disruption and reduce neuroinflammation more effectively than MSCs in experimental autoimmune encephalomyelitis

Authors: Narges Maleki, Maryam Rezapour Kalkhorann, Mohammad Sajad Sajad Emami Aleagha, Amir Emami, Abdolamir Allameh

Background The anti-aging protein, Klotho, has been shown to exert neuroprotective effects in neurodegenerative disorders. This study was designed to evaluate the effects of MSCs engineered with secreted Klotho (SKL-MSCs) on neuroinflammation in experimental autoimmune encephalomyelitis (EAE) mouse model and to investigate underlying molecular mechanisms. Methods EAE was induced in female C57BL/6 mice, and animals were then randomized to receive PBS, MSCs, or SKL-MSCs at the onset of disease. BBB permeability assay was performed. The mRNA and protein expression of inflammatory factors was detected in the brain of animals by real-time PCR and immunohistochemistry, respectively. The mRNA and protein expression of BBB-associated factors was detected in the brain of animals by real-time PCR and Western blotting, respectively. Results The results showed that SKL-MSCs slowed EAE progression and attenuated the disease severity more effectively than MSCs. SKL-MSCs also decreased the expression of TNF-α, IFN-γ, and IL-17 but increased the expression of IL-10 more potently than MSCs in the brain of EAE animals. Furthermore, SKL-MSCs reduced BBB permeability more significantly than MSCs, which was accompanied by decreased levels of BBB-associated factors, ICAM-1, VCAM-1, MMP-9, and CCL2, in the brain of EAE animals. However, in mice treated with MSCs, the reduction in the expression of BBB-associated factors was limited to ICAM-1 and MMP-9. Conclusions Our study highlighted the significantly greater therapeutic power of SKL-MSCs compared with MSCs in attenuating EAE disease severity and reducing neuroinflammation, which might be mediated through a more marked reduction in the BBB permeability and BBB-associated factors expression levels in the brain of animals.

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MSCs engineered with secreted Klotho alleviate blood–brain barrier disruption and reduce neuroinflammation more effectively than MSCs in experimental autoimmune encephalomyelitis

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Original ResearchVol. 16, None • pp. 254DOI: 10.1186/s13287-025-04358-7

Combining sodium-glucose co-transporter-2 inhibitor with mesenchymal stem cells and brown adipose tissue (BAT) and white adipose tissue (WAT) transplantation to mitigate the progression of diabetic kidney disease: a pre-clinical approach

Authors: Stephany Beyerstedt, Marcella L. Franco, Alanah K. G. Carlos, Jaqueline Arjona, Gleice R. Josefi-Rocha, Bruno S. Barbosa, Maria Theresa A. Balby-Rocha, Andrei Furlan da Silva, Tuany Marques Reiter Alves, Melise Oliveira Mariano, Maria Clara Soares Klein, Érika Bevilaqua Rangel

Introduction The increasing prevalence of Diabetes Mellitus (DM) correlates with a rising incidence of Diabetic Kidney Disease (DKD). DKD, a multifactorial condition, is characterized by activation of the renin–angiotensin–aldosterone system (RAAS), with angiotensin II playing a significant role in podocyte injury. While conventional treatments show potential in mitigating DKD progression, a combination of strategies is required to both impede its development and repair damaged structures. Methods In this study, we explored the brown adipose tissue (BAT) and white adipose tissue (WAT) transplantation, and the use of bone marrow mesenchymal stem cell therapy (BM-MSC) combined with sodium-glucose co-transporter-2 (SGLT2) inhibitor treatment and calorie restriction in the BTBRob/ob model, recognized as a robust representation of DKD featuring hyperglycemia, obesity, time-dependent albuminuria, and histological changes. Results Our primary findings revealed enhanced blood glucose control through combined cell therapy, diminished mesangial matrix expansion, alleviated tissue oxidative stress, preserved podocyte numbers, and an upregulation of podocyte structural markers and components of the RAAS renoprotective axis. Conclusion BM-MSC therapy demonstrates considerable promise as a combined treatment for mitigating DKD progression, with similar findings observed for BAT and WAT transplantation.

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Combining sodium-glucose co-transporter-2 inhibitor with mesenchymal stem cells and brown adipose tissue (BAT) and white adipose tissue (WAT) transplantation to mitigate the progression of diabetic kidney disease: a pre-clinical approach

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Original ResearchVol. 16, Issue 1 • pp. 22DOI: 10.1186/s13287-025-04146-3

Dental pulp stem cell-derived intracellular vesicles prevent orthodontic relapse by inhibiting PI3K/Akt/NF-κB-mediated osteoclast activity

Authors: Boyuan Peng, Ziwei Li, Yong Cheng, Henghua Jiang, Qingsong Ye, Guangli Han

Background Orthodontic relapse, the undesired deviation of teeth from their corrected positions, remains a significant challenge in clinical orthodontics. Incomplete periodontal bone remodeling has been identified as a key factor in this process. Despite decades of research, currently there are no effective strategies to prevent relapse. Methods We isolated and identified dental pulp stem cell-derived intracellular vesicles (DPSC-IV) from human dental pulp tissue. To investigate its effect, DPSC-IV was added to osteoblast or osteoclast differentiation medium. During the orthodontic retention period, DPSC-IV was administrated to rats by subgingival injection. Relapse distance and relapse rate were calculated to evaluate DPSC-IV's ability to prevent relapse. Additionally, Western blot analysis were used to examine DPSC-IV's inhibitory effect on osteoclast differentiation. Results DPSC-IV significantly promoted osteoblast differentiation and inhibited osteoclast differentiation. Application of DPSC-IV during retention resulted in a significant reduction in both relapse distance and relapse rate, with improved periodontal structure and decreased osteoclast activity. This effect was mediated by the PI3K/Akt/NF-κB signaling pathway and could be reversed by the PI3K activator insulin-like growth factor-1 (IGF-1). Conclusion This study highlights the potential of DPSC-IV as a novel preventive approach against orthodontic relapse, offering a novel strategy for maintaining long-term orthodontic stability.

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Dental pulp stem cell-derived intracellular vesicles prevent orthodontic relapse by inhibiting PI3K/Akt/NF-κB-mediated osteoclast activity

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Original ResearchVol. 16, Issue 1 • pp. 417DOI: 10.1186/s13287-025-04547-4

Geometrical constraints dictate assembly and phenotype of human iPSC-derived motoneuronal spheroids

Authors: Eleonora Mello, Stefano Sorrentino, Alessio Bucciarelli, Ermanno Cordelli, Elisa De Luca, Haakon Nygaard, Stefan Wendt, Alberto Rainer, Giuseppe Gigli, Lorenzo Moroni, Alessandro Polini, Pamela Mozetic

Background Neuronal spheroids represent an easy and versatile solution to model neuronal tissue in vitro. Conventional approaches to generate spheroids lack accurate size control, scalability, and customizability. This is even more exacerbated in case of pluripotent stem cell (PSC) derived spheroids, which remain challenging to standardize. Microwell devices address these limitations, providing an optimal balance between accessibility and scalability. With the aim of optimizing culture conditions, we parametrically investigated the role of microwell geometry on the formation and maturation of iPSC-derived motor neuron precursor (MNP) spheroids. Methods We developed a customizable mold device using Digital Light Processing (DLP) 3D printing to fabricate agarose microwell arrays with distinct aspect ratios for culturing hiPSC-derived MNP spheroids with high reproducibility. We generated nine different pyramidal microwell array geometries for culturing size-controlled spheroids in the 40–140 μm diameter range. We then evaluated the differential expression of genes related to cell proliferation and motor-neuron differentiation as function of microwell geometry and spheroid size. Results Our results indicate that spheroid size is significantly influenced by the microwell geometry, reliably due to cell partitioning at the seeding stage. Expression of proliferation and differentiation markers, such as motor neuron and pancreas homeobox 1 (MNX1) and Islet-1 (ISL1) transcription factors, is also dependent on microwell geometry and spheroid morphological descriptors. Conclusion Our approach enables the scalable production of size-controlled MNP spheroids and underscores the effect of geometrical confinement on regulating motor neuron differentiation.

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Geometrical constraints dictate assembly and phenotype of human iPSC-derived motoneuronal spheroids

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Original ResearchVol. 16, None • pp. 441DOI: 10.1186/s13287-025-04565-2

Correction: DPSCs modulate synovial macrophage polarization and efferocytosis via PINK1/Parkin-dependent mitophagy

Authors: Jinjin Ma, Xinyu Wang, Dalei Sun, Jiali Chen, Linyi Zhou, Kaiao Zou, Xinxin Ni, Hongting Jin, Jun Lin

This correction article addresses an error in the scale of the control group image in Fig. 4E of the original article. The corrected image is provided. The original article can be found online at https://doi.org/10.1186/s13287-025-04468-2.

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Correction: DPSCs modulate synovial macrophage polarization and efferocytosis via PINK1/Parkin-dependent mitophagy

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Original ResearchVol. 16, Issue 1 • pp. 50DOI: 10.1186/s13287-025-04165-0

Paracrine activity of Smurf1-silenced mesenchymal stem cells enhances bone regeneration and reduces bone loss in postmenopausal osteoporosis

Authors: Alberto González-González, Itziar Álvarez-Iglesias, Daniel García-Sánchez, Monica Dotta, Ricardo Reyes, Ana Alfonso-Fernández, Alfonso Bolado-Carrancio, Patricia Díaz-Rodríguez, María Isabel Pérez-Núñez, José Carlos Rodríguez-Rey, Jesús Delgado-Calle, Flor M. Pérez-Campo

Background: Osteoporosis (OP), characterized by reduced bone mass and mineral density, is a global metabolic disorder that severely impacts the quality of life in affected individuals. Although current pharmacological treatments are effective, their long-term use is often associated with adverse effects, highlighting the need for safer, more sustainable therapeutic strategies. This study investigates the pro-osteogenic and anti-resorptive potential of the secretome from Smurf1-silenced mesenchymal stem cells (MSCs) as a promising cell-free therapy for bone regeneration. Methods: Conditioned media (CM) from Smurf1-silenced rat (rCM-Smur1) and human MSCs (hCM-Smurf1) was collected and analyzed. Pro-osteogenic potential was assessed by measuring in vitro mineralization in human and rat MSCs cultures. In vivo, studies were conducted using a rat ectopic bone formation model and a post-menopausal osteoporotic mouse model. Additionally, primary human osteoporotic MSCs were preconditioned with hCM-Smurf1, and their osteogenic capacity was compared to that induced by BMP2 treatment. Ex vivo, human bone explants were treated with hCM-Smurf1 to assess anti-resorptive effects. Proteomic analysis of the soluble and vesicular CM fractions identified key proteins involved in bone regeneration. Results: CM from Smurf1-silenced MSCs significantly enhanced mineralization in vitro and bone formation in vivo. Preconditioning human osteoporotic MSCs with hCM-Smurf1 significantly increases in vitro mineralization, with levels comparable to those achieved with BMP2 treatment. Additionally, in ex vivo human bone cultures, treatment with hCM-Smurf1 significantly reduced RANKL expression without affecting OPG levels, indicating an anti-resorptive effect. In vivo, CM from Smurf1-silenced MSCs significantly increased bone formation in a rat ectopic model, and its local administration reduced trabecular bone loss by 50% in a post-menopausal osteoporotic mouse model after a single administration within just four weeks. Proteomic analysis revealed both soluble and vesicular fractions of hCM-Smurf1 were enriched with proteins essential for ossification and extracellular matrix organization, enhancing osteogenic differentiation. Conclusions: The Smurf1-silenced MSCs’ secretome shows potent osteogenic and anti-resorptive effects, significantly enhancing bone formation and reducing bone loss. This study provides compelling evidence for the therapeutic potential of Smurf1-silenced MSC-derived secretome as a non-toxic and targeted treatment for osteoporosis. These findings warrant further in vivo studies and clinical trials to validate its therapeutic efficacy and safety.

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Paracrine activity of Smurf1-silenced mesenchymal stem cells enhances bone regeneration and reduces bone loss in postmenopausal osteoporosis

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Original ResearchVol. 16, None • pp. 314DOI: 10.1186/s13287-025-04457-5

Mesenchymal stem cell-derived exosomes–a promising therapeutic approach to improve neurocognitive disorders in chronic obstructive pulmonary disease

Authors: Hui Xiao, Xiao Yu, Yushan Liu, Wenhua Jiang, Xiaoting Meng, Zhiyong Dong, Fang Wang

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide and is often accompanied by neurocognitive disorders. It seriously affects the quality of life and treatment outcome of patients. COPD-induced neurocognitive disorders (COPD-NCDs) are driven by systemic inflammation, blood-brain barrier (BBB) disruption, and chronic hypoxia, but there is currently no effective treatment to prevent or reverse cognitive decline. Mesenchymal stem cell-derived exosomes (MSC-Exos) are nanoscale extracellular vesicles with unique bioactivity, which have shown great potential in the fields of nervous system diseases, respiratory diseases, bone and joint diseases. Different from traditional cell therapies, MSC-Exos have the advantages of non-immunogenicity, non-tumorigenicity, high stability and biocompatibility. In addition, MSC-Exos can also cross the BBB, regulate neuroinflammation, promote neurogenesis, enhance myelination and improve synaptic plasticity, thereby addressing the multifaceted pathogenesis of central nervous system (CNS) diseases. In this review, we first summarize the pathogenic mechanism of COPD-NCDs, and then summarize the multiple mechanisms of MSC-Exos improving NCDs based on the efficacy of MSC-Exos on other CNS diseases, emphasizing the theoretical basis and unique potential of MSC-Exos as a treatment for COPD-NCDs. Finally, we prospected the future research directions and potential problems of applying MSC-Exos to treat COPD-NCDs, future research should focus on optimizing the large-scale preparation of MSC-Exos, exploring their long-term safety, and advancing clinical translation to address the unmet needs of COPD-NCDs patients.

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Mesenchymal stem cell-derived exosomes–a promising therapeutic approach to improve neurocognitive disorders in chronic obstructive pulmonary disease

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Original ResearchVol. 16, None • pp. 635DOI: 10.1186/s13287-025-04429-9

Toward clinically relevant models of complex perianal fistulas: refining preclinical evaluation for exosome-based therapies

Authors: Qianqian Ye, Qingming Wang

This letter commends Lu et al. for their innovative preclinical study demonstrating the therapeutic potential of hUCMSCs-Exo in treating complex perianal fistulas (CPF) through HIF-1α/TGF-β/Smad pathway activation, collagen synthesis, and gut microbiota modulation. While acknowledging the study's significant advances, the authors highlight three translational considerations: anatomical disparities between rodent models and humans, long-term safety concerns, and the need for comparative efficacy studies. To refine the experimental model, they propose enhancements in fistula stability and tracking, including extending wire retention to 6–8 weeks, biweekly intraluminal E. coli injections, and using contrast-enhanced MRI for longitudinal monitoring. These refinements aim to better mimic human fibrotic progression and improve clinical predictability.

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Toward clinically relevant models of complex perianal fistulas: refining preclinical evaluation for exosome-based therapies

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Original ResearchVol. 16, None • pp. 80DOI: 10.1186/s13287-025-04203-x

Exosomes from adipose-derived stem cells accelerate wound healing by increasing the release of IL-33 from macrophages

Authors: Yichen Wang, Hongfan Ding, Ruiqi Bai, Qiang Li, Boyuan Ren, Pianpian Lin, Chengfei Li, Minliang Chen, Xiao Xu

Background Mesenchymal stem cell (MSC) -derived exosomes, especially adipose-derived mesenchymal stem cell exosomes (ADSC-Exos), have emerged as a promising alternative for skin damage repair with anti-inflammatory, angiogenic and cell proliferation effects while overcoming some of the limitations of MSC. However, the mechanism by which ADSC-Exos regulates inflammatory cells during wound healing remains unclear. This study investigated how ADSC-Exos regulate macrophages to promote wound healing. Methods ADSC-Exos were isolated using ultracentrifugation, with subsequent quantification of exosomes particle number. To investigate their role in wound healing, the effects of ADSC-Exos on inflammation, angiogenesis, collagen deposition and macrophage polarization were evaluated through immunohistochemical staining, immunofluorescence and western blotting. Changes in gene expression associated with ADSC-Exos-induced macrophage polarization were analyzed using qPCR. RNA sequencing was performed to identify differentially expressed genes affected by ADSC-Exos. The critical role of IL-33 in the wound healing process was further confirmed using Il33−/− mice. Additionally, co-culture experiments were conducted to explore the effects of IL-33 on keratinocyte proliferation, collagen deposition and epithelialization. Results ADSC-Exos inhibited the expression of TNF-α and IL-6, induced M2 macrophage polarization, promoted collagen deposition and angiogenesis, and accelerated wound healing. RNA sequencing identified IL-33 as a key mediator in this process. In Il33−/− mice, impaired wound healing and decreased M2 macrophage polarization were observed. The co-culture experiments showed that IL-33 enhanced keratinocyte function through activation of the Wnt/β-catenin signaling pathway. These findings highlight the therapeutic potential of ADSC-Exos in wound healing by modulating IL-33. Conclusions ADSC-Exos promote wound healing by regulating macrophage polarization and enhancing IL-33 release which drives keratinocyte proliferation, collagen deposition and epithelialization via the Wnt/β-catenin

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Exosomes from adipose-derived stem cells accelerate wound healing by increasing the release of IL-33 from macrophages

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Original ResearchVol. 16, Issue 1 • pp. 26DOI: 10.1186/s13287-025-04145-4

Migrasomes derived from human umbilical cord mesenchymal stem cells: a new therapeutic agent for ovalbumin-induced asthma in mice

Authors: Weifeng Gu, Tingting Zheng, Wen Li, Xinkai Luo, Xiaowei Xu, Ying Wang, Chaoming Mao, Yongbin Ma, Liyang Dong

Background Asthma is a prevalent respiratory disease, and its management remains largely unsatisfactory. Mesenchymal stem cells (MSCs) have been demonstrated to be efficacious in reducing airway inflammation in experimental allergic diseases, representing a potential alternative treatment for asthma. Migrasomes are recently identified extracellular vesicles (EVs) generated in migrating cells and facilitate intercellular communication. The objective of this study was to investigate the therapeutic effects of migrasomes obtained from MSC in a model of asthma. Methods Migrasomes produced by human umbilical cord MSCs (hUCMSCs) were isolated by sequential centrifugation. Characterization of hUCMSC-derived migrasomes were carried out by transmission electron microscopy and western blot analysis. The therapeutic effects of migrasomes on airway inflammation in ovalbumin (OVA)-induced asthmatic mice were evaluated by hematoxylin-eosin (HE) and periodic-acid schiff (PAS) staining, and their mechanism were further testified by immunofluorescent staining, real-time PCR and flow cytometry. Results Here, we showed that inhibition of migrasomes’ production dramatically impaired the anti-inflammatory effects of hUCMSCs in OVA animals, as evidenced by a notable increase in both the infiltration of inflammatory cells and the number of epithelial goblet cells. We successfully isolated hUCMSC-migrasomes, which were morphologically intact and positive for the specific migrasomes markers. The administration of hUCMSC-migrasomes was observed to significantly ameliorate the symptoms of airway inflammation and mucus production in asthmatic mice. Additionally, the expression of Th2 cytokines (IL-4, IL-5 and IL-13) were found to be reduced, while the activation of dendritic cells (DCs) was inhibited. HUCMSC-migrasomes could possibly be delivered to lung region after injection, and were able to be taken in by DCs both in vivo and in vitro. Notably, in vitro, migraosmes decreased the capacity of

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Migrasomes derived from human umbilical cord mesenchymal stem cells: a new therapeutic agent for ovalbumin-induced asthma in mice

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Original ResearchVol. 16, None • pp. 654DOI: 10.1186/s13287-025-04773-w

Research on the mechanism of human umbilical cord mesenchymal stem cells and their extracellular vesicles in the treatment of common reproductive diseases

Authors: Xin Guo, Bingchun Liu, Peixin Xu, Hong Chen, Jing Gao, Dongmei Yao, Xin Li, Yurong Wang, Tong Wang, Hongrui Yao, Shuwei Qiao, Jile Huge, Jianlong Yuan

Reproductive system disorders significantly contribute to infertility, and traditional or conventional treatments often have limited efficacy in addressing this issue. In recent years, stem cell therapy has emerged as an alternative therapeutic strategy owing to its various advantages. Human umbilical cord mesenchymal stem cells (hUC-MSCs) are pivotal in tissue repair owing to their robust proliferative capacity, potent immunomodulatory effects, low immunogenicity, and paracrine actions. Extracellular vesicles (EVs), the primary mediators of paracrine functions, exhibit therapeutic effects similar to those of hUC-MSCs. Consequently, numerous researchers have investigated the application of hUC-MSCs and their EVs in treating reproductive disorders. These cells have the potential to restore fertility by mitigating oxidative stress, excessive autophagy, and ferroptosis in tissues, while promoting the expression of anti-inflammatory factors and vascular remodeling. However, hUC-MSCs present significant limitations compared to EVs, including higher tumorigenicity and low infusion efficiency. Consequently, EVs may emerge as the primary alternative therapy, while hUC-MSCs hold promise as a therapeutic option with potential applications in regenerative medicine.

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Research on the mechanism of human umbilical cord mesenchymal stem cells and their extracellular vesicles in the treatment of common reproductive diseases

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Original ResearchVol. 16, Issue 1 • pp. 9DOI: 10.1186/s13287-024-04090-8

Combination of rapamycin and adipose-derived mesenchymal stromal cells enhances therapeutic potential for osteoarthritis

Authors: Damien Veret, Gautier Tejedor, Esther Perez, Alison Chomette, Maylis Farno, Rosanna Ferreira-Lopez, Louis Dagneaux, Yves-Marie Pers, Christian Jorgsensen, Claire Gondeau, Jean-Marc Brondello

Background The regenerative potential of mesenchymal stromal/stem cells (MSCs) has been extensively studied in clinical trials in the past decade. However, despite the promising regenerative properties documented in preclinical studies, for instance in osteoarthritis (OA), the therapeutic translation of these results in patients has not been fully conclusive. One factor contributing to this therapeutic barrier could be the presence of senescent cells in OA joints. Methods This study evaluated a novel approach to OA treatment by combining adipose tissue-derived MSCs (AD-MSCs) with rapamycin, a clinically approved immunosuppressive drug with anti-senescence properties. First, rapamycin effects on senescence and fibrosis markers were investigated in freshly isolated OA chondrocytes by immunostaining. Next, the in vitro differentiation capacities of AD-MSCs, their regulatory immune functions on activated immune cells and their regenerative effects on OA chondrocyte signature were assessed in the presence of rapamycin. Results In OA chondrocytes, rapamycin reduced the senescence marker p15INK4B and the fibrosis marker COL1A1 without affecting the expression of the master chondrogenic markers SOX9 and COL2. Rapamycin also enhanced AD-MSC differentiation into chondrocytes and reduced their differentiation into adipocytes. In addition, rapamycin improved AD-MSC immunoregulatory functions by promoting the expression of immunosuppressive factors, such as IDO1, PTGS2 and also CD274 (encoding PD-L1). Finally, RNA sequencing analysis showed that in the presence of rapamycin, AD-MSCs displayed improved chondroprotective regenerative effects on co-cultured OA chondrocytes. Conclusions Our findings suggest that the rapamycin and AD-MSC combination enhances the therapeutic efficacy of these cells in senescence-driven degenerative diseases such as OA, notably by improving their anti-fibrotic and anti-inflammatory properties.

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Combination of rapamycin and adipose-derived mesenchymal stromal cells enhances therapeutic potential for osteoarthritis

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Original ResearchVol. 16, None • pp. 393DOI: 10.1186/s13287-025-04523-y

The therapeutic potential of mesenchymal stem cells in intestinal diseases: from mechanisms to clinical translation

Authors: Jia-Zhi Yang, Li-Yan He, Xian-Zhou Lu

Current therapeutic interventions for intestinal pathologies, including anti-inflammatory agents, immunosuppressants, and surgical procedures, frequently incur substantial adverse effects, elevated recurrence rates, and suboptimal tissue regeneration. Cellular therapy has emerged as a paradigm-shifting strategy, capitalizing on regenerative potential and immunomodulatory properties. Mesenchymal stem cells (MSCs), distinguished by their potent immunoregulatory capacity and multipotent differentiation plasticity, have recently demonstrated remarkable therapeutic promise in inflammatory bowel disease (IBD), ischemia–reperfusion injury, oncological interventions, and radio-chemotherapy-induced complications. This systematic review critically evaluates MSC biological characteristics, clinical translation progress, and cutting-edge advancements in tissue engineering applications. Mechanistic insights into MSC-mediated intestinal repair are elucidated, with particular emphasis on emerging evidence suggesting MSC-derived exosomes may modulate ZBP1-associated H3K27 acetylation to attenuate intestinal epithelial apoptosis—a novel epigenetic regulatory axis for gastrointestinal restitution. Future translational trajectories and clinical implementation challenges are comprehensively discussed.

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The therapeutic potential of mesenchymal stem cells in intestinal diseases: from mechanisms to clinical translation

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Original ResearchVol. 16, Issue 213 • pp. 1-22DOI: 10.1186/s13287-025-04326-1

Targeting prominin-2/BACH1/GLS pathway to inhibit oxidative stress-induced ferroptosis of bone mesenchymal stem cells

Authors: Yuzhu Xu, Lele Zhang, Xuanfei Xu, Yuao Tao, Pengfei Xue, Yuntao Wang, Renjie Chai, Xiaotao Wu

Suppressing bone mesenchymal stem cell (BMSC) ferroptosis is expected to optimize BMSCs-based therapy for intervertebral disc degeneration (IVDD). Our previous study revealed that Prominin-2 could protect against ferroptosis by decreasing cellular Fe2+ content and inhibiting transcription regulator protein BACH1 (BACH1) expression. In this study we probed the molecular mechanisms underlying the Prominin-2/BACH1 pathway in BMSC ferroptosis. Using an array of in vitro and in vivo experiments we found that heat shock factor protein 1 (HSF1) activates PROM2 (encoding protein Prominin-2) transcription and elevated Prominin-2 expression. Furthermore, we showed that Prominin-2 attenuates ferroptosis induced by tert-butyl hydroperoxide (TBHP) through promoting BACH1 ubiquitination and degradation. Inhibition of BACH1 expression reversed TBHP-stimulated down expression of glutaminase kidney isoform, mitochondrial (GLS), which plays a crucial role in protecting BMSCs against ferroptosis. Targeting the Prominin-2/BACH1 axis has also been shown to improve BMSC survival post-transplantation and mitigate IVDD progression by inhibiting ferroptosis. Our results support a new mechanistic insight into the regulation of the Prominin-2/BACH1/GLS pathway in BMSC ferroptosis. These finding could lead to potential therapeutic targets to improve the survival of engrafted BMSCs under oxidative stress circumstances.

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Targeting prominin-2/BACH1/GLS pathway to inhibit oxidative stress-induced ferroptosis of bone mesenchymal stem cells

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Original ResearchVol. 16, None • pp. 473DOI: 10.1186/s13287-025-04589-8

Donor-dependent regulation of type II and X collagen deposition by early modulation of miR-335-5p and miR-1246 during chondrogenic commitment

Authors: Franziska L. Breulmann, Silvia A. Berger, Elena Della Bella, Martin J. Stoddart

Background Identification of biomarkers to predict the risk of healing delays are of huge clinical interest since 10% of fracture patients progress to delayed or non-union. During endochondral ossification, which takes place in mechanically unstable regions, the bone regenerates through a cartilage intermediate. We previously identified miR-1246, miR-335-5p and miR-193a-5p as fracture-related biomarkers in patient serum, but they appear not to have a functional role in an in vitro model of direct ossification. However, their involvement in other processes related to fracture healing cannot be ruled out and the most common healing process in fracture repair is secondary healing by way of endochondral ossification. Therefore, this study aims to explore the role of miR-1246, miR-335-5p and miR-193a-5p during in vitro endochondral differentiation of human bone marrow-derived mesenchymal stromal cells (BMSCs). Methods The activity of miR-1246, miR-335-5p, and miR-193a-5p was transiently inhibited just before pellet formation and the start of chondrogenic differentiation in human BMSCs (n=5 donors), serving as a model for early endochondral ossification. The effect of miRNA inhibition was assessed by histology (Safranin O/Fast Green), immunohistochemistry (type II and type X collagen), and gene expression analysis by bulk RNA sequencing and RT-qPCR. Results Inhibition of miR-1246 and miR-335-5p enhanced chondrogenic and hypertrophic differentiation in BMSCs from three out of five donors, while miR-193a-5p inhibition had minimal effect. Donors were categorized as “responders” or “non-responders” based on histological and gene expression profiles. RNA sequencing and RT-qPCR identified differentially expressed genes, including a 1.6 and 1.5-fold upregulation of GDF5 and CCN5 respectively (p<0.05) and downregulation of SKIL (fold change: 1.3, p=0.0563) after miR-335-5p inhibition, while the same genes were unaltered by miRNA inhibition in non-responders, suggesting donor-specific responses to miRNA inhibition during early chondrogenesis.

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Donor-dependent regulation of type II and X collagen deposition by early modulation of miR-335-5p and miR-1246 during chondrogenic commitment

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Original ResearchVol. 16, None • pp. 386DOI: 10.1186/s13287-025-04519-8

The role of stem cell-derived exosomes in regulating pyroptosis for disease therapy

Authors: Yilin Guo, Qiyin Liu, Jingjun Yang, Yan Gao, Ying Liu

Pyroptosis, a form of programmed cell death, is widely involved in the occurrence and development of various diseases. Its mechanism relies primarily on the activation of pyroptosis proteins, making their expression levels crucial biological markers for assessing the degree of pyroptosis. In the progression of diseases, regulating pyroptosis can alleviate tissue damage and promote repair; in cancer treatment, inducing pyroptosis in cancer cells is also considered a potential therapeutic strategy. In recent years, acellular therapies have garnered significant attention in clinical research, with extracellular vesicles (EVs) (such as exosomes) emerging as novel acellular therapeutic tools. Exosomes exhibit remarkable potential for the treatment of various diseases, particularly in regulating pyroptosis. Owing to their diverse biological functions, exosomes derived from different sources of mesenchymal stem cells (MSCs) play distinct roles in treating different diseases. This review systematically summarizes the role and application prospects of MSC-derived exosomes in regulating pyroptosis for disease treatment. Studies have indicated that MSC-derived exosomes not only precisely regulate the process of pyroptosis but also offer new insights and methods for future disease therapies, and therefore, MSC-derived exosomes possess significant clinical translational value.

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The role of stem cell-derived exosomes in regulating pyroptosis for disease therapy

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Original ResearchVol. 16, None • pp. 684DOI: 10.1186/s13287-025-04701-y

Single-cell RNA sequencing identifies PD-L1+ mesenchymal stem cells with enhanced immunomodulatory capacity and alleviated the degree of ectopic new bone formation in ankylosing spondylitis

Authors: Xiqing Luo, Liuzhong Zhou, Xianghui Wen, Jinwei Li, Dong Liu, Budian Liu, Shenghui Wen, Jieruo Gu

Background This study systematically evaluated the immunomodulatory function of PD-L1-positive mesenchymal stem cells (PD-L1(+) MSCs) using single-cell RNA sequencing (scRNA-seq) and investigated their roles in suppressing inflammation and regulating pathological bone formation in curdlan-induced SKG ankylosing spondylitis (AS) mouse models. Methods scRNA-seq identified MSC subpopulations with high immunomodulatory capacity and key biomarker PD-L1 for subpopulation classification. In vitro co-culture experiments were conducted to evaluate the effects of MSC subpopulations on T-cell proliferation and TNF-α levels. In vivo experiments were performed in forty-eight SKG mouse models to analyze the effects of MSC subpopulations on joint inflammation scores, T-cell subset proportions, inflammatory cytokines, histopathology, and pathological bone formation. Results scRNA-seq revealed significant heterogeneity in MSCs under inflammatory stimulation, with the immunomodulatory subpopulation exhibiting high expression of PD-L1 and IDO. In vitro experiments demonstrated that PD-L1(+) MSCs significantly suppressed T-cell proliferation and reduced TNF-α levels. Joint redness and swelling scores showed that the PD-L1(+) MSC group exhibited the most significant improvement in arthritis, while the IL-17Ai, PD-L1(-) MSC, and MSC groups also effectively reduced inflammation, with significantly lower scores than the model control(MC) group. Histological analysis revealed severe inflammatory cell infiltration in the MC group, while the IL-17Ai, PD-L1(+) MSC, and MSC groups exhibited reduced infiltration. Immunohistochemical analysis further confirmed these findings, with PD-L1(+) MSCs exhibiting a significant reduction in TNF-α and IL-17A-positive cells (P < 0.0001 and P < 0.01, respectively). PD-L1(+) MSCs regulated immune responses by reducing Th17 cell proportions, increasing Th2 and Treg cell proportions, and significantly lowering pro-inflammatory cytokines IFN-γ, IL-17A, and TNF-α. MicroCT analysis indicated that the PD-L1(+) MSC, MSC, and IL-17Ai group effectively suppressed pathological bone formation.

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Single-cell RNA sequencing identifies PD-L1+ mesenchymal stem cells with enhanced immunomodulatory capacity and alleviated the degree of ectopic new bone formation in ankylosing spondylitis

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Original ResearchVol. 16, Issue 1 • pp. 141DOI: 10.1186/s13287-025-04267-9

Enhancing myelinogenesis through LIN28A rescues impaired cognition in PWMI mice

Authors: Xuan Wu, Zhechun Hu, Huimin Yue, Chao Wang, Jie Li, Yinxiang Yang, Zuo Luan, Liang Wang, Ying Shen, Yan Gu

Background: In premature newborn infants, preterm white matter injury (PWMI) causes motor and cognitive disabilities. Accumulating evidence suggests that PWMI may result from defected differentiation of oligodendrocyte precursor cells (OPCs) and impaired maturation of oligodendrocytes. However, the underlying mechanisms remain unclear. Methods: Using RNAscope, we analyzed the expression level of RNA-binding protein LIN28A in individual OPCs. Knockout of one or both alleles of Lin28a in OPCs was achieved by administrating tamoxifen to NG2CreER::Ai14::Lin28aflox/+ or NG2CreER::Ai14::Lin28aflox/flox mice. Lentivirus expressing FLEX-Lin28a was used in NG2CreER mice to overexpress LIN28A in OPCs. A series of behavioral tests were performed to assess the cognitive functions of mice. Two-tailed unpaired t-tests was carried out for statistical analysis between groups. Results: We found that the expression of Lin28a was decreased in OPCs in a PWMI mouse model. Knockout of one or both alleles of Lin28a in OPCs postnatally resulted in reduced OPC differentiation, decreased myelinogenesis and impaired cognitive functions. Supplementing LIN28A in OPCs postnatally was able to promote OPC differentiation and enhance myelinogenesis, thus rescuing the cognitive functions in PWMI mice. Conclusion: Our study reveals that LIN28A is critical in regulating postnatal myelinogenesis. Overexpression of LIN28A in OPCs rescues cognitive deficits in PWMI mice by promoting myelinogenesis, thus providing a potential strategy for the treatment of PWMI.

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Enhancing myelinogenesis through LIN28A rescues impaired cognition in PWMI mice

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Original ResearchVol. 16, None • pp. 324DOI: 10.1186/s13287-025-04472-6

Mesenchymal stromal cell secretome reduces lung injury and thrombo-inflammation induced by SARS-CoV-2 spike protein

Authors: Anna Pezzotta, Alessandra Bovio, Barbara Imberti, Monica Locatelli, Daniela Corna, Domenico Cerullo, Sara Gastoldi, Ariela Benigni, Giuseppe Remuzzi, Marina Morigi, Luca Perico

Severe COVID-19 is characterized by thrombo-inflammatory processes within the lung microvasculature. In pursuit of effective treatments, clinical studies explored mesenchymal stromal cells (MSCs) as a promising approach due to their anti-inflammatory, immunomodulatory, and regenerative properties, through their paracrine action. Here, we tested the conditioned medium (CM) derived from human umbilical cord (UC)-MSCs in acute lung injury induced by the spike protein subunit 1 (S1) in ACE2-humanized male mice. Injection of CM significantly limited S1-induced lung injury, edema, and fibrosis. This was associated with reduced vascular dysfunction, in terms of restored thrombomodulin levels and decreased von Willebrand (vWF) expression. By preserving endothelial glycocalyx, CM reduced complement C3 accumulation, favoring factor H binding on the lung microvasculature. Reduced oxidative stress, nuclear NF-κB p65 accumulation, and inflammatory cell infiltration were also observed in response to CM in S1-injected mice. In vitro, CM counteracted thrombo-inflammation by preserving thrombomodulin, as well as limiting vWF expression, due to endothelial glycocalyx recovery. CM reduced nuclear translocation of NF-κB p65 and its downstream targets, ICAM-1 and P-selectin, translating in decreased C3 deposits, platelet aggregation, and leukocyte adhesion on S1-challenged endothelial cells. Collectively, these data indicate that UC-MSC-derived secretome represents a promising therapy in COVID-19 due to its potent anti-thrombotic and anti-inflammatory effects on lung microcirculation.

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Mesenchymal stromal cell secretome reduces lung injury and thrombo-inflammation induced by SARS-CoV-2 spike protein

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Original ResearchVol. 16, None • pp. 149DOI: 10.1186/s13287-025-04274-w

LincRNA-ASAO promotes dental pulp repair through interacting with PTBP1 to increase ALPL alternative splicing

Authors: Fuchun Fang, Xiaolan Guo, Sitong Liu, Longrui Dang, Zehao Chen, Yumeng Yang, Lu Chen, Jiahao Lin, Wei Qiu, Zhao Chen, Buling Wu

Background Alternative splicing not only expands the genetic encoding of genes but also determines cellular activities. This study aimed to elucidate the regulation mechanism and biological functions of lincRNA-ASAO in the process of odontogenesis-related genes alternative splicing mediated odontogenic differentiation of hDPSCs. Methods RACE, RNA-seq, FISH and bioinformatics techniques were used to identify novel lincRNA-ASAO. ALP staining, alizarin red staining, qRT-PCR and western blot were used to identify the role of lincRNA-ASAO in regulating the odontoblast differentiation of hDPSCs. The binding protein PTBP1 of lincRNA-ASAO was screened by RNA-Pull-down, protein profiling and bioinformatics. The target gene ALPL of lincRNA-ASAO/PTBP1 was identified by RNA-seq, bioinformatics technology and DNA agarose gel electrophoresis. FISH, IF, PAR-CLIP and bioinformatics techniques were used to determine the roles of lincRNA-ASAO, PTBP1 and ALPL pre-mRNA in the odontoblast differentiation of hDPSCs. Results We identified a novel lincRNA-ASAO that could promote the odontogenic differentiation of human Dental Pulp Stem Cells (hDPSCs). And, the interaction between lincRNA-ASAO and alternative splicing factor PTBP1 promoted the odontoblast differentiation of hDPSCs. In addition, lincRNA-ASAO forms duplexes with ALPL pre-mRNA, targeting PTBP1 to exonic splicing silencer (ESS) of ALPL and regulating exon 2 skipping. Notably, lincRNA-ASAO/PTBP1 regulated ALPL production to increase the type 2 splice variant, which promoted the odontoblast differentiation of hDPSCs. Conclusions We have identified the novel lincRNA-ASAO, which can promote the odontoblast differentiation of hDPSCs. The mechanism study found that lincRNA-ASAO/PTBP1 mediated the exon 2 skipping of ALPL pre-mRNA, resulting in the type 2 splice variant of ALPL. Our results enrich the understanding of lncRNAs and alternative splicing in regulating the odontoblast differentiation of hDPSCs, and provide clues to improve the clinical therapeutic potential of hDPSCs for dental pulp restoration.

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LincRNA-ASAO promotes dental pulp repair through interacting with PTBP1 to increase ALPL alternative splicing

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Original ResearchVol. 16, Issue 440 • pp. 1-17DOI: 10.1186/s13287-025-04540-x

Trained human bone marrow mesenchymal stem cells restore tissue immuno-microenvironment in fulminant hepatic failure mice

Authors: Bingqi Li, Xiaofei Zeng, Jing Jiang, Qian Zhou, Li Tong, Xi Liang, Jiaojiao Xin, Xi Chen, Xiao Wu, Yuheng Kong, Shiwen Ma, Jinjin Luo, Wei Qiang, Bing Zhu, Xinhua Luo, Jun Li, Dongyan Shi

Background Trained immunity with human bone marrow mesenchymal stem cells (hBMSC) is a promising approach to liver regeneration. This study aimed to clarify the trained-hBMSC (T-hBMSC) in restoring tissue immuno-microenvironment in fulminant hepatic failure (FHF) mice. Methods hBMSC trained with tumor necrosis factor-α and interferon-γ were phenotypically characterized in vitro. FHF mouse models were established in male Balb/c mice via tail vein injection of concanavalin A. The therapeutic potential of T-hBMSC was evaluated through transplantation into FHF mice. Transcriptomic analysis was performed to elucidate the mechanism of liver regeneration post-transplantation of T-hBMSC. Results T-hBMSC with the characteristics of trilineage differentiation potential showed that pro-inflammatory (IL1β, IL8, both p < 0.0001) and immunoregulatory genes (PDL1, IDO1, both p < 0.0001) were significantly upregulated compared to untrained-hBMSC (UT-hBMSC). Time-trajectory analysis revealed downregulation of pro-inflammatory genes (IL6, IL8, and IL1α) and upregulation of immunomodulatory genes (IDO1) in T-hBMSC upon mimic-stimulation, characterized by distinct transcriptional programs. The liver function (ALT, AST) and inflammatory cytokines (IL6, MCP1, both p < 0.01) levels were significantly improved in the T-hBMSC-treated mice. The survival status of the T-hBMSC group was superior to the UT-hBMSC group, although there was no statistical significance. Histological analysis confirmed reduced necrosis and fewer infiltrating CD45+ immune cells in the T-hBMSC-treated mice. Significant downregulation of immune response (TNF & IL-17 signaling pathways and neutrophil chemotaxis) and upregulation of metabolic pathways were observed in the T-hBMSC group, associated with enhanced liver regeneration. The proportion of anti-inflammatory F4/80+CD163+ macrophages was increased in the liver of T-hBMSC group.

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Trained human bone marrow mesenchymal stem cells restore tissue immuno-microenvironment in fulminant hepatic failure mice

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Original ResearchVol. 16, None • pp. 549DOI: 10.1186/s13287-025-04713-8

Retraction Note: Human fetal skin-derived stem cell secretome enhances radiation-induced skin injury therapeutic effects by promoting angiogenesis

Authors: Xiaoli Rong, Jiannan Li, Yanyan Yang, Liyan Shi, Tiechao Jiang

The Editors-in-Chief have retracted this article because of concerns regarding the figures presented in this work. An investigation conducted after its publication discovered the following issues: The Control/CD73 panel in Fig. 1 appears to overlap with the Control/Oct4 in the same figure; Figure 5e appears to overlap with the EGF/α-SMA panel in Fig. 6a in [1]; The bottom portion of Fig. 5g appears to overlap with the top portion of the MSC-CM/α-SMA panel in Fig. 6a in [1]; The panels in question represent cells or tissues subject to different experimental conditions. The Editors-in-Chief therefore no longer have confidence in the integrity of the research presented in this article. The authors have not replied to correspondence from the Publisher about this retraction.

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Retraction Note: Human fetal skin-derived stem cell secretome enhances radiation-induced skin injury therapeutic effects by promoting angiogenesis

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Original ResearchVol. 16, None • pp. 236DOI: 10.1186/s13287-025-04378-3

The therapeutic efficacy comparison of MSCs derived different tissues unveilings anti-apoptosis more crucial than angiogenesis in treating acute myocardial infarction

Authors: Mingjie Pan, Yueyue Xu, Yaping Wang, Yue Jiang, Yuanyuan Xie, Chenxu Tai, Wenqing Wang, Bin Wang

Background Myocardial infarction (MI) is a severe disease that often associated with impaired angiogenesis and increased myocardial apoptosis. Mesenchymal stromal cells (MSCs) have been a promising candidate for treating myocardial infarction. However, functional heterogeneity of MSCs leads to inconsistent therapeutic efficiency and the current MSCs-based therapy lacks the concept and implementation of precision medicine. In this study, we compared the cardioprotective effect of UCMSCs and ADMSCs targeting the angiogenesis in a mouse MI model and screened out optimum MSCs candidate for precise clinical application. Methods The gene expression profiles of UCMSCs and ADMSCs were investigated through RNA sequencing analysis. To compare their angiogenic potential, we performed tube formation assay, Matrigel plug assays, and aortic ring assay, and analyzed pro-angiogenic genes via qPCR. Subsequently, UCMSCs and ADMSCs were respectively injected into myocardium after MI surgery in mice. On day 28 post-MI, echocardiography was performed to assess cardiac function. Histological analysis was performed to assess MSCs retention, angiogenesis, and myocardial apoptosis. Additionally, the anti-apoptosis effects mediated by MSCs were further evaluated using flow cytometry in hypoxia H9C2 and HL-1 cells. Results The RNA sequencing analysis revealed differences in gene expression related to angiogenesis and apoptosis pathways between UCMSCs and ADMSCs. UCMSCs presented greater pro-angiogenesis activity than ADMSCs in vitro and in vivo. Both of UCMSCs and ADMSCs improved cardiac function, decreased infarction area and inhibited cardiomyocyte apoptosis while promoting angiogenesis post-MI in mice. Notably, ADMSCs exerted a better cardioprotective function than UCMSCs and stronger anti-apoptotic effect on residual cardiomyocytes.

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The therapeutic efficacy comparison of MSCs derived different tissues unveilings anti-apoptosis more crucial than angiogenesis in treating acute myocardial infarction

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Original ResearchVol. 16, None • pp. 507DOI: 10.1186/s13287-025-04637-3

E2 pretreatment alleviates aggregation of intravenously injected mesenchymal stem cells in TBI by regulating BRG1 to affect adhesion

Authors: Wangan Li, Xiangyu Wang, Zhiming Feng, Shiting Hua, Xiaoxiong Zou, Zelin Lai, Yingqian Cai, Yuxi Zou, Yanping Tang, Cai Lin, Guobiao Luo, Xiaolin Cai, Xiaodan Jiang

Background Human umbilical cord mesenchymal stem cells (hUMSCs) are considered an effective prospect for treating TBI, but they tend to accumulate in the lungs after intravenous injection, hindering further clinical translation. Brahma-related gene 1(BRG1) can be influenced by estrogen to regulate adhesion, and ourprevious studies have found that the expression of BRG1 in lungs increases after TBI. However, the relationship between BRG1, estrogen, TBI, and stem cell lung aggregation is not clear. Methods By regulating the expression levels of BRG1 in vascular endothelial cells and hUMSCs, Western Blot and immunohistochemistry were used to explore its changes in adhesion and possible mechanisms; used in vivo bioluminescenece imaging analysis, real-time tracking the distribution of stem cells after transplantation; and therapeutic drug E2 is introduced to observe the effect of changes in BRG1 expression on the aggregation of hUMSCs in the lungs of model animals, as well as the therapeutic effect of E2-pretreated hUMSCs on inflammation after TBI. Results After TBI, the retention of hUMSCs in the lungs was higher in the TBI groups than in the Sham groups, and the level of BRG1 in lung was higher in the TBI groups than in the Sham groups; the expression of BRG1 in HUVECs, HPAECs, and hUMSCs treated with TNF-α and LPS were higher than those in the control groups, showing dose- and time-dependent effects. E2 can inhibit the expression of BRG1 and adhesion proteins; after intervention with estrogen receptor inhibitor (ICI 182780) and NF-κ B inhibitor SC75741, BRG1 expression increased and adhesion protein decreased; E2-pretreated MSCs can reduce pulmonary retention, and has no adverse effects on the inflammatory response for TBI.

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E2 pretreatment alleviates aggregation of intravenously injected mesenchymal stem cells in TBI by regulating BRG1 to affect adhesion

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Original ResearchVol. 16, None • pp. 66DOI: 10.1186/s13287-025-04151-6

Development and evaluation of siRNA-mediated gene silencing strategies for ADO2 therapy utilizing iPSCs model and DMPC-SPIONs delivery system

Authors: Jiajun Xu, Gengshuo Chen, Chune Mo, Yu Sha, Sha Luo, Minglin Ou

Background Autosomal dominant osteodystrophy type II (ADO2) is an inherited disease characterized by an abnormal increase in bone mineral density, and CLCN7 (R286W) is its most common causative mutation. The aim of this study was to explore the new idea of siRNA technology applied to the in vitro treatment of ADO2. Methods Urinary-derived cells from ADO2 patients were collected to establish induced pluripotent stem cells (iPSCs) model. The siRNA targeting CLCN7 (R286W) mutant mRNA was designed. the cytotoxicity of the delivery vector DMPC-SPIONs was comprehensively evaluated by CCK-8 assay, flow cytometry and scratch assay. Finally, qPCR was utilized to verify the post-transcriptional silencing effect of siRNAs. Results We found that DMPC-SPIONs had low cytotoxicity and were able to effectively deliver siRNAs into ADO2-iPSCs. qPCR confirmed that siRNA-DMPC-SPIONs were able to significantly reduce the expression level of mutant CLCN7 (66%), while there was no significant effect on the expression of wild-type CLCN7. Conclusions This study developed a gene silencing strategy based on siRNAs and DMPC-SPIONs, which provides a potential new approach for the treatment of ADO2 and demonstrates the potential application of siRNA technology in the treatment of autosomal dominant genetic diseases. Innovative statements In this study, we used the established ADO2-iPSCs using patient's urine-derived cells to explore the safety and efficacy of siRNA technology based on the principle of RNA interference for ADO2 treatment for the first time. In addition, we chose DMPC-SPIONs as the delivery vehicle for siRNA, which cleverly exploits the advantages of nanoparticles such as superparamagnetism, low cytotoxicity, and good bio-histocompatibility.

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Development and evaluation of siRNA-mediated gene silencing strategies for ADO2 therapy utilizing iPSCs model and DMPC-SPIONs delivery system

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