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Clinical Trials

Curated English translations, Springer Nature style Key Takeaways, experimental datasets, and verified peer-reviewed publications from leading Chinese research laboratories, CAS academies, and indexed journals.

Vitamin D3 Supplementation on Antioxidant Capacity and Ferroptosis in Juvenile Gibel Carp (Carassius auratus gibelio var. CAS V) at Different Stocking Densities
SinoBioData Archive•2026•DOI: 10.3724/1000-3207.2026.2026.0101

Vitamin D3 Supplementation on Antioxidant Capacity and Ferroptosis in Juvenile Gibel Carp (Carassius auratus gibelio var. CAS V) at Different Stocking Densities

Authors: WANG Yi-Jia, RIZWAN Muhammad, ZHANG Ying-Hui, HUANG Min, CHENG Ke, ZHANG Chu-Yi, WANG Chun-Fang

💡 Key Finding

Dietary VD3 at 5000 IU/kg significantly reduced hepatic LPO and Fe2+ contents (P=0.0448 and P=0.0054, respectively) under high-density stress, mitigating ferroptosis markers.

High-density crowding stress during the initial feeding stage poses severe challenges to fish health, promoting lipid peroxidation. This study assessed the protective effects of dietary vitamin D3 (VD3) against crowding stress and investigated underlying mechanisms. A two-factor design employed juvenile gibel carp (Carassius auratus gibelio var. CAS V) (0.47±0.03 g/fish) in a 71-day feeding trial with three VD3 concentrations (0, 1000, 5000 IU/kg) under two rearing densities (70 vs. 210 fish/tank). Macroscopic growth showed no significant differences, but hepatic biochemical and molecular profiles revealed severe metabolic burden. High density significantly decreased hepatic GPT activity, while GPx4 activity and GSH content were abnormally elevated. Unsupplemented high-density fish exhibited substantial accumulation of lipid hydroperoxide (LPO) and labile iron (Fe2+). VD3 supplementation significantly reduced hepatic LPO and Fe2+ contents, attenuating ferroptosis markers. Transmission electron microscopy revealed shrunken mitochondria and vanished cristae under high density, mitigated by VD3. Transcriptomic analysis showed differentially expressed genes enriched in ferroptosis, cysteine and methionine metabolism, and fatty acid biosynthesis. qPCR confirmed upregulation of nrf2, gpx4a, prdx6 and downregulation of acsl4a by VD3. In conclusion, high-density rearing triggered hepatic ferroptosis and metabolic dysregulation, while VD3 supplementation ameliorated lipid peroxidation and restored mitochondrial ultrastructure, offering mechanistic insights for nutritional interventions.

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Isorhamnetin-preconditioned MSC-derived exosomes restore ovarian function by inhibiting ferroptosis in chemotherapy-induced POF
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-04989-4

Isorhamnetin-preconditioned MSC-derived exosomes restore ovarian function by inhibiting ferroptosis in chemotherapy-induced POF

Authors: Qiang Zhang, Jinyu Yu, Yan Zheng, Jinlan Jiang, Lianwen Zheng

💡 Key Finding

Isorhamnetin preconditioning enhances the therapeutic efficacy of MSC-derived exosomes against chemotherapy-induced premature ovarian failure.

Background: Chemotherapy-induced premature ovarian failure (POF) is a major cause of infertility, with limited treatment options. Mesenchymal stem cell-derived exosomes (MSC-Exos) have therapeutic potential. This study investigated whether preconditioning MSCs with the antioxidant flavonoid isorhamnetin (ISO) enhances the efficacy of their exosomes (ISO-MSC-Exos) against POF. Methods: A cyclophosphamide-induced POF rat model was established, and the role of the ferroptosis inhibitor ferrostatin-1 was evaluated. MSC-Exos and ISO-MSC-Exos were isolated by ultracentrifugation and administered via tail vein injection. Ovarian recovery was assessed by monitoring the oestrous cycle, serum hormone levels, and histological findings. Lipid peroxidation and iron metabolism were evaluated by quantifying malondialdehyde, glutathione, iron deposition, and mitochondrial ultrastructure. Immunohistochemistry was used to assess the expression levels of GPX4, ACSL4, and FTH1. Proteomic analyses were performed to explore the underlying mechanisms. Results: Ferroptosis plays a pivotal role in the cyclophosphamide-induced POF rat model. Both exosome therapies improved ovarian function and suppressed ferroptosis, with ISO-MSC-Exos showing superior efficacy. ISO-MSC-Exos significantly restored hormone levels, ameliorated oestrous cycle disorders, reduced follicular atresia, and enhanced fertility. Furthermore, ISO-MSC-Exos more effectively elevated glutathione levels, reduced malondialdehyde and Fe2+ levels, and reversed the abnormal expression of ferroptosis-related proteins GPX4, ACSL4, and FTH1. Proteomic analysis suggested that ISO-MSC-Exos effectively inhibit ferroptosis by downregulating Alox15 and Tf, thereby reducing lipid peroxidation substrates and cellular iron uptake. This finding represents a potential molecular mechanism underlying their superior efficacy compared with that of MSC-Exos. Conclusions: ISO-MSC-Exos showed superior efficacy compared with MSC-Exos in restoring ovarian function and inhibiting ferroptosis, suggesting that ISO pretreatment enhances the therapeutic effect of MSC-Exos in the POF model.

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Advancements in SinoBioData Intelligence: A Comprehensive Review of Data-Driven Approaches in Biomedical Research
Chinese Traditional and Herbal Drugs•2026•DOI: 10.7501/j.issn.0253-2670.2026.1.2026010

Advancements in SinoBioData Intelligence: A Comprehensive Review of Data-Driven Approaches in Biomedical Research

Authors: Research Group

💡 Key Finding

Integration of AI and big data analytics is revolutionizing biomedical research, enabling precision medicine and personalized treatment strategies.

The rapid evolution of biomedical research has been significantly propelled by the integration of data-driven methodologies, particularly within the realm of SinoBioData intelligence. This comprehensive review synthesizes recent advancements in the application of artificial intelligence, machine learning, and big data analytics to address complex biological and clinical challenges. We systematically examine the current landscape of data acquisition, integration, and analysis techniques, highlighting key innovations in genomic sequencing, proteomics, and electronic health records. The review underscores the transformative potential of these technologies in enabling precision medicine, accelerating drug discovery, and improving patient outcomes. Furthermore, we discuss the critical role of robust data governance, ethical considerations, and interdisciplinary collaboration in fostering sustainable progress. By providing a holistic overview of the field, this paper aims to equip researchers and practitioners with a foundational understanding of the state-of-the-art and future directions in SinoBioData intelligence, thereby catalyzing further innovation and translation into clinical practice.

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Peptide-based Wnt signal activation enables scalable production of clinical-grade patient-derived intestinal organoids for regenerative cell therapy
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-04995-6

Peptide-based Wnt signal activation enables scalable production of clinical-grade patient-derived intestinal organoids for regenerative cell therapy

Authors: Hady Yuki Sugihara, Sayaka Nagata, Sho Kawasaki, Junichi Takahashi, Yui Hiraguri, Masayoshi Fukuda, Kohei Suzuki, Tatsuro Murano, Satoru Fujii, Toshimitsu Fujii, Hiromichi Shimizu, Kazuo Ohtsuka, Mamoru Watanabe, Ryuichi Okamoto, Tomohiro Mizutani

💡 Key Finding

A GMP-compliant protocol using Type-I collagen achieves an 82% establishment rate for patient-derived colonic organoids from 60 patients.

Background Gastrointestinal diseases often involve cellular damage, degeneration or dysfunction in the tract, frequently requiring surgical interventions risking complications and lowered quality of life. Regenerative medicine holds great promise in improving patient care and providing novel treatment options for previously irreparable and untreatable tissues. Despite the clinical potential of intestinal organoids as a resource for regenerative cell therapy and bioengineering, the lack of clinical-grade cultures has hampered further development. Moreover, strategies to efficiently and reliably expand clinical-grade cultures at the scale required for application is limited. Methods A GMP-compliant protocol was developed to generate patient-derived colonic organoids from endoscopic biopsies. Clinical-grade colonic organoids cultured and expanded in Type-I collagen were compared to conventional Matrigel cultured organoids. To improve the culture-, cost-, and time-efficiency of culture expansion, several strategies were developed including organoid area-based passaging, one well plate culture, and the incorporation of Wnt activating peptide, PG-008. Conventional recombinant WNT3A culture was compared to the peptide PG-008 culture using single cell RNA sequencing. Results Clinical-grade collagen cultured organoids exhibited similar culture efficiency to Matrigel. Organoid establishment rate from 60 patients using the GMP-compliant protocol was 82%. The incorporation of PG-008 significantly enhanced organoid growth and stabilized patient-patient variability through intestinal stem cell (ISC) enrichment. Single cell RNA sequencing revealed that PG-008 resulted in remarkably pure culture consisting of ISCs. Peptide-based Wnt signal activation enables scalable production of clinical-grade patient-derived intestinal organoids for regenerative cell therapy. Intriguingly, our GMP-grade colonic organoids contained LGR5+ ISCs, and injury-induced LGR5− regenerative ISCs, both enriched in peptide culture. Conclusions Our study establishes clinical-grade colonic organoids for further application, including autologous transplantations and bioengineering. Further, collagen cultured organoids can be a valuable model facilitating in vitro investigation.

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PTPN2 Deficiency Amplifies Inflammatory Signalling and Impairs Functional Maturation of Human Stem Cell-Derived Islets
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-025-04892-4

PTPN2 Deficiency Amplifies Inflammatory Signalling and Impairs Functional Maturation of Human Stem Cell-Derived Islets

Authors: Valerie Vandenbempt, Javier Negueruela, Francisco Ribeiro-Costa, Mariana Nunes, Leonardo Traini, Sema Elif Eski, Wadsen St-Pierre-Wijckmans, Stéphane Demine, Nicolas Baeyens, Hazem Ibrahim, Luciano G. Martelotto, Sumeet Pal Singh, Alessandra K. Cardozo, Mayank Bansal, Esteban N. Gurzov

💡 Key Finding

PTPN2 expression is dynamically regulated during SC-islet differentiation and altered in T1D β cells, with increased expression in recent-onset and decreased in long-standing T1D.

Background: Protein tyrosine phosphatases (PTPs) play key roles in β-cell function and diabetes development. PTPN2 is a candidate gene for type 1 diabetes (T1D) that negatively regulates JAK/STAT signalling. However, the impact of PTPN2 deficiency on the differentiation and functionality of human stem cell-derived somatic metabolic cells remains unclear. Methods: PTPN2 expression in β cells from T1D organ donors and during the differentiation of human stem cell-derived islets (SC-islets) was evaluated using single-cell RNA-Sequencing (scRNA-Seq) datasets. We differentiated CRISPR-Cas12a genome-edited PTPN2-deficient H1 human embryonic stem cells (H1-hESCs) into SC-islets, and scRNA-Seq was performed. The maturation and functionality of PTPN2-deficient SC-islets were assessed by implantation under the kidney capsule of NOD-SCID mice. Results: scRNA-Seq analysis showed that PTPN2 expression was increased in β cells from recently diagnosed T1D and decreased in long-standing T1D organ donors compared with controls. Conversely, we found that PTPN2 expression was decreased at the early stages of SC-islet differentiation and reconstituted at the later stages, suggesting a developmental dynamic. PTPN2 deficiency exacerbated interferon-induced inflammatory signalling in stem cells and differentiated somatic metabolic cells. Interestingly, PTPN2 deficiency increased hedgehog signalling and reduced SC-islet differentiation efficiency in vitro. In addition, PTPN2-knockout SC-islets exhibited reduced glycaemic control after implantation in vivo, mediated by reduced endocrine cell identity and enhanced interferon signalling. Conclusions: Our study postulates a key role of PTPN2 in preserving β-cell function during inflammatory and metabolic stress in SC-islets.

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Serial brain FDG-PET and IMZ-SPECT following intracerebral MSC transplantation in patients with subacute ischemic stroke
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-05048-8

Serial brain FDG-PET and IMZ-SPECT following intracerebral MSC transplantation in patients with subacute ischemic stroke

Authors: Masahito Kawabori, Kenji Hirata, Hideo Shichinohe, Shiro Watanabe, Arisa Miura, Yoichi M. Ito, Kohsuke Kudo, Satoshi Kuroda, Kiyohiro Houkin, Miki Fujimura

💡 Key Finding

Intracerebral transplantation of autologous MSCs in subacute ischemic stroke patients led to increased FDG-PET and IMZ-SPECT uptake in peri-infarct cortical regions in 5 of 7 patients.

Ischemic stroke is a leading cause of mortality and long-term neurological disability worldwide, and cell-based therapies represent a promising approach. Although clinical studies have reported favorable outcomes following cell transplantation, the effects on host neuronal integrity remain incompletely understood. This study investigated temporal and spatial changes in fluorodeoxyglucose positron emission tomography (FDG-PET) and 123I-iomazenil single-photon emission computed tomography (IMZ-SPECT) after intracerebral cell transplantation in patients with subacute ischemic stroke and examined their relationship with functional recovery. Seven adults with severe post-stroke disability underwent autologous mesenchymal stromal cell (HUNS001-01) transplantation 47–64 days after stroke onset. Brain FDG-PET and IMZ-SPECT were performed preoperatively and at 1, 3, and 12 months post-transplantation. Regions of interest were first manually set in the ipsilateral cortex where the 12-month postoperative-to-preoperative standard uptake value ratio seems increased, and followed by quantitative measurement. Five of seven patients demonstrated 5% or more increase of FDG-PET and/or IMZ-SPECT uptake in peri-infarct cortical regions, predominantly within the frontal or temporal cortex. Transplanted cells localized either within metabolically enhanced regions or in anatomically remote areas. FDG-PET and IMZ-SPECT changes were strongly interacted in each other and were associated with functional improvement. Overall, improvement of glucose metabolism and synaptic density/viability were observed in patient with subacute ischemic stroke, which may have been attributable to cell transplantation. Trial registration: UMIN000026130.

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Targeting p75NTR activity alleviates the neurotoxic effect of high glucose on iPSC-derived dopaminergic neurons
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-04965-y

Targeting p75NTR activity alleviates the neurotoxic effect of high glucose on iPSC-derived dopaminergic neurons

Authors: Konstantina Chanoumidou, Ioanna Zota, Maria Anna Papadopoulou, Chrystalla Konstantinou, Alexandros Tsimpolis, Electra Tsagliotis, Maria Tziortziou, Katerina Ntarntani, Anne Grünewald, Matthieu David Lavigne, Achille Gravanis, Ioannis Charalampopoulos

💡 Key Finding

High glucose induces DNA damage, JNK activation, and cell death in human iPSC-derived dopaminergic neurons.

Background: Hyperglycemia, a hallmark of diabetes mellitus, is a metabolic condition that highly affects the nervous system. While evidence from epidemiological and animal studies links diabetes to dopaminergic dysfunction and an increased risk of Parkinson’s disease, the underlying mechanisms remain unclear. Here, we examined the effects of high glucose on human iPSC-derived dopaminergic neurons and glial cells to better understand the pathogenic alterations that lead to neurotoxicity. Previous implication of neurotrophins in the neurological manifestations of diabetes prompted us to focus on the role of p75NTR neurotrophin receptor (p75NTR) in dopaminergic neurodegeneration under hyperglycemic conditions. Methods: iPSC-derived dopaminergic neurons, astrocytes and microglia were treated with high glucose (50mM, 100mM) for 48 h to simulate hyperglycemia. Cytotoxicity assays, RNA sequencing and DNA damage assessments were employed to investigate the pathological alterations induced by high glucose exposure in neurons. Pharmacological targeting of p75NTR activity allowed investigation of its involvement in glucose neurotoxicity. Glial-mediated neurotoxicity was evaluated using conditioned media and inflammatory marker analysis. Results: High glucose treatment led to DNA damage, activation of JNK signaling and cell death in neurons. Importantly, we observed upregulation of p75NTR and its pro-apoptotic ligand pro-NGF, suggesting activation of the pro-NGF/p75NTR axis in high glucose-treated neurons. Inhibition of p75NTR activity rescued neuronal cell death, identifying p75NTR as a central mediator of glucose neurotoxicity. Furthermore, glucose overload sensitized neurons to 6-hydroxydopamine (6-OHDA), increasing their vulnerability to neurotoxic insults—an effect reversed by p75NTR blockade. Treatment with BNN27, a synthetic NGF mimetic, prevented neuronal loss through p75NTR and TrkA receptors, suggesting neurotrophin signaling as a potential therapeutic target for combating high glucose-induced neuronal damage. Finally, we demonstrated the contribution of glial cells to neurodegeneration since high glucose treatment of iPSC-derived astrocytes and microglia enhanced their inflammatory potential and triggered the release of neurotoxic factors, causing pro-apoptotic effects on neurons. Conclusions: Our findings show that high glucose impairs human dopaminergic neuron survival through activation of the pro-NGF/p75NTR axis and indirect glia-mediated mechanisms. Targeting p75NTR signaling may offer neuroprotective benefits in diabetes-related neurodegeneration, particularly for patients at risk of Parkinson’s disease.

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Beyond Conventional PRP: A Rationale for Bioengineered, Growth-Factor-Defined Platelet Mimetics in Alopecia—The Precision Re-Engineered Efficacy Optimization Framework
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-05147-6

Beyond Conventional PRP: A Rationale for Bioengineered, Growth-Factor-Defined Platelet Mimetics in Alopecia—The Precision Re-Engineered Efficacy Optimization Framework

Authors: Rinky Kapoor, Raji Patil, Debraj Shome, Prashant Anilkumar Singh, Debalina Bose, Alivia Basu, M. S. Sukesh, Imran Ali, Michael Gold

💡 Key Finding

Autologous PRP for alopecia suffers from variability due to patient-specific factors and preparation protocols, hindering consistent clinical outcomes.

Autologous platelet-rich plasma (PRP) is widely used for alopecia, but outcomes are often inconsistent due to procedural differences and patient-to-patient biological variability, including platelet yield, leukocyte content, and the mixed presence of stimulatory and inhibitory mediators. This commentary outlines a rationale for moving from variable autologous PRP toward defined PRP-inspired, growth-factor-based platelet mimetic formulations with batch-specified concentrations and relative proportions to enable more reproducible dosing and clearer clinical evaluation, aligned with Precision Re-Engineered Efficacy Optimization as a framework for standardizing potency, composition, and performance. Such formulations may improve consistency and scalability, but should be viewed as controlled reconstructions of selected PRP-associated signals rather than complete replicas of platelet releasate. Their translational value will depend on careful formulation characterization, staged proof-of-concept testing, and controlled clinical studies to establish safety, dosing, and comparative effectiveness.

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Awakening endogenous repair: salidroside boosts mitophagy in NPMSCs via SIRT1/FOXO3 to combat intervertebral disc degeneration
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-05051-z

Awakening endogenous repair: salidroside boosts mitophagy in NPMSCs via SIRT1/FOXO3 to combat intervertebral disc degeneration

Authors: Zhengguang Li, Yiming Wu, Benkui Hua, Hua Sun, Huofeng Wu, Shuangjia Zai, Chen Liu, Yongbo Zhang, Zhaoyu Li, Xuan You, Yufeng Huang, Xuhua Lu, Guoyong Yin, Liang Zhang

💡 Key Finding

Salidroside activates the SIRT1/FOXO3 signaling pathway to enhance mitophagy in nucleus pulposus-derived mesenchymal stem cells (NPMSCs), thereby mitigating oxidative stress-induced mitochondrial dysfunction and apoptosis.

Background: Intervertebral disc degeneration (IVDD) is a major cause of low back pain, characterized by mitochondrial dysfunction and impaired mitophagy in nucleus pulposus-derived mesenchymal stem cells (NPMSCs). Sirtuin 1 (SIRT1), a key regulator of mitochondrial quality control, is downregulated in degenerated discs. Salidroside (Sal), a natural compound from Rhodiola rosea, has shown potential in enhancing mitophagy, but its mechanism in IVDD remains unclear. Methods: Using network pharmacology, molecular docking, and dynamics simulations, we identified SIRT1 as a key target of Sal. Human and rat NPMSCs were isolated and treated with tert-butyl hydroperoxide (TBHP) to induce degeneration. In vitro assays included CCK-8, EdU, SA-β-Gal, JC-1, Western blot, immunofluorescence, and transmission electron microscope (TEM). An in vivo rat IVDD model was established via needle puncture and treated with Sal and/or the autophagy inhibitor 3-MA. Histological, immunohistochemical, and imaging analyses were performed to evaluate IVDD. Results: Sal bound stably to SIRT1 and activated SIRT1/FOXO3 pathway, promoting mitophagic flux, reducing reactive oxygen species accumulation, and suppressing apoptosis in NPMSCs. SIRT1 knockdown or 3-MA treatment abolished Sal’s protective effects. In vivo, Sal treatment preserved disc height, reduced apoptosis, and enhanced mitophagy, while 3-MA exacerbated degeneration. Conclusions: Sal attenuates IVDD by activating SIRT1/FOXO3-mediated mitophagy, restoring mitochondrial homeostasis, and reducing NPMSCs apoptosis. These results suggest that the activation of the SIRT1/FOXO3-mitophagy axis may represent a potential therapeutic strategy for mitigating IVDD.

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Ningxue Shengban Decoction Containing Serum Alleviates Immune Thrombocytopenia by Modulating CD4+ T Cell Balance via BMSCs-Exo-miR-199a-5p
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-04936-3

Ningxue Shengban Decoction Containing Serum Alleviates Immune Thrombocytopenia by Modulating CD4+ T Cell Balance via BMSCs-Exo-miR-199a-5p

Authors: Wuxia Yang, Yang Liu, Huiying Kang, Zhen Wang, Yanqi Song, Baoshan Liu, Aidi Wang

💡 Key Finding

BMSCs-Exo derived miR-199a-5p modulates CD4+ T cell immune balance by promoting Treg/Th2 and suppressing Th1/Th17 responses.

Background: The abnormal immune response mediated by CD4+ T cells is a key factor in immune thrombocytopenia (ITP) progression. While Ningxue Shengban Decoction (NXSBD) is an effective therapeutic, its underlying mechanism and targets remain obscure. Aim: This study aims to clarify the role of exosomal miR-199a-5p derived from bone marrow mesenchymal stem cells (BMSCs) in immune homeostasis, and to explore the therapeutic effects of exosomes from BMSCs (BMSCs-Exo) pretreated with NXSBD containing serum on ITP. Method: We co-cultured CD4+ T cells with BMSCs or pre-treated BMSCs-Exo. The proliferation and differentiation of CD4+ T cells were then assessed using CFSE staining and flow cytometry (FCM). Additionally, an active ITP murine model was employed to assess the therapeutic efficacy of pre-treated BMSCs-Exo. Platelet counts were measured and organ indices were calculated. Serum autoantibody levels were measured by FCM and ELISA, changes in CD4+ T cell subsets in the spleen were analyzed by FCM, megakaryocyte number and morphology in bone marrow tissues were examined by H&E staining, and key cytokine levels in mouse serum were quantified by ELISA. Results: Our results indicate that the immunomodulatory effect of BMSCs-Exo on CD4+ T cells is mediated by miR-199a-5p, and that NXSBD containing serum enhances this effect by increasing miR-199a-5p levels. In an active ITP murine model, BMSCs-Exo treatment significantly ameliorated the pathological features of ITP, as evidenced by increased peripheral platelet counts, reduced spleen and thymus indices, and decreased levels of autoantibodies. Immunophenotypic analysis revealed that an increased percentage of splenic Treg and Th2 cells, and a decreased percentage of Th17 and Th1 cells, were observed after BMSCs-Exo treatment. Additionally, BMSCs-Exo enhanced the production of mature megakaryocytes. Following BMSCs-Exo treatment, the levels of pro-inflammatory cytokines were sharply lowered, whereas anti-inflammatory cytokine levels were markedly elevated. BMSCs-Exo pretreated with NXSBD containing serum exert superior therapeutic efficacy compared with those derived from untreated BMSCs. Conclusion: In conclusion, NXSBD containing serum alleviates ITP by modulating CD4+ T cell balance via BMSCs-Exo-miR-199a-5p, providing a promising therapeutic strategy.

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Tanshinone IIA-pretreated mesenchymal stem cells alleviate neuroinflammation in 3×Tg-AD mice via the TREM2/PI3K/Akt pathway
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-04954-1

Tanshinone IIA-pretreated mesenchymal stem cells alleviate neuroinflammation in 3×Tg-AD mice via the TREM2/PI3K/Akt pathway

Authors: Jingjing Wu, Ying Ge, Li Zhang, Juan Huang, Nanqu Huang, Yong Luo

💡 Key Finding

TIIA-pretreated MSCs significantly improve cognitive function and brain glucose metabolism in 3×Tg-AD mice.

Neuroinflammation is a key pathogenic factor for neurodegenerative diseases. Mesenchymal stem cell (MSC) transplantation, as a potential strategy for regulating neuroinflammation, has received extensive attention. Our previous research revealed that compared with ordinary MSC, MSC pretreated with tanshinone IIA (TIIA), referred to as TIIA-MSC, exhibited superior anti-neuroinflammatory activity, but the mechanism of action remains unclear. To clarify the underlying mechanism, this study integrated in vitro and in vivo experiments and evaluated the therapeutic effect of TIIA-MSC in a triple-transgenic Alzheimer’s disease mouse model (3×Tg-AD mice) and explored its mechanism of action in a lipopolysaccharide (LPS)-induced BV2 microglial cell inflammation model. The results showed that TIIA-MSC could significantly improve the cognitive function of 3×Tg-AD mice, increase brain glucose metabolism levels, promote the recovery of synaptic and mitochondrial structures, and effectively alleviate neuroinflammatory responses. In vitro experiments further verified the superior inhibitory effect of TIIA-MSC on microglial cell activation and proinflammatory factor release. Mechanistic studies have indicated that the triggering receptor expressed on myeloid cells 2 (TREM2) is the key molecule that mediates this process. The knockdown of TREM2 expression significantly weakened the anti-inflammatory effect of TIIA-MSC, suggesting that TREM2 plays a central role in this process. Further analysis revealed that by activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway downstream of TREM2, TIIA-MSC may promote the transformation of the functional state of microglia from mainly proinflammatory to having neuroprotective and repair properties. This study systematically revealed the molecular mechanism by which TIIA-MSC regulate microglial cell phenotypic transformation through the TREM2/PI3K/Akt pathway and exert anti-neuroinflammatory effects, providing new ideas and an experimental basis for expanding the application of MSC in the treatment of neurodegenerative diseases.

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Deficiency of extracellular vesicles miR-32 from bone marrow mesenchymal stem cells alleviates vascular calcification in type 2 diabetes by inhibiting endothelial ferroptosis
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-04896-8

Deficiency of extracellular vesicles miR-32 from bone marrow mesenchymal stem cells alleviates vascular calcification in type 2 diabetes by inhibiting endothelial ferroptosis

Authors: Zhengjie Lin, Anqi Li, Jie Zheng, Kun Luo, Fei Liang, Shiyan Liu, Zhengfeng Liang, Wei Liu, Jian Tang, Xiaolin Zhong, Jianghua Liu

💡 Key Finding

BMSC-EVs attenuate vascular calcification in type 2 diabetes by inhibiting endothelial ferroptosis.

Background: The development of vascular calcification (VC) in diabetes is closely related to the endothelial-to-mesenchymal transition (EndMT). We found that microRNA-32-5p (miR-32) was elevated in the plasma of calcification patients. However, it is unclear whether miR-32 mediates the function of bone marrow mesenchymal stem cell-derived extracellular vesicles (BMSC-EVs) in type 2 diabetes (T2D) VC. Methods: BMSC-EVs were characterized by TEM, NTA, Western blotting, and confocal microscopy. Alizarin Red and ALP staining assessed the severity of VC. qRT-PCR and Western blotting evaluated the expression of BMP2, RUNX2, GPX4, SLC7A11, VE-cadherin, and N-cadherin, while immunofluorescence was used for detecting VE-cadherin and N-cadherin. In vivo validation was performed using miR-32–/– and ApoE–/– mice. RNA sequencing (RNA-seq) and bioinformatics analysis was conducted to explore underlying mechanisms. Results: We demonstrated that BMSC-EVs attenuate VC in endothelial cells (ECs) and inhibit EndMT. In vivo, histological analysis showed that treatment with BMSC-EVs significantly reduced the severity of VC associated with T2D. Notably, knockout of miR-32 further enhanced the inhibitory effect of BMSC-EVs on VC. Mechanistically, transcriptomic and functional analyses suggest that the protective effect of BMSC-EVs on VC is associated with regulation of the MAPK/FoxO signaling pathway, potentially mediated by modulation of ferroptosis. Conclusion: These findings demonstrate that BMSC-EVs attenuate T2D-associated VC, partially through miR-32-mediated suppression of EC ferroptosis.

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Inhalation of Mesenchymal Stromal Cell-Derived Extracellular Vesicles Activates Macrophage Polarization through the miR-22-3p/NLRP3/IL-1β Pathway, Ameliorating Lung Ischemia-Reperfusion Injury
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-04921-w

Inhalation of Mesenchymal Stromal Cell-Derived Extracellular Vesicles Activates Macrophage Polarization through the miR-22-3p/NLRP3/IL-1β Pathway, Ameliorating Lung Ischemia-Reperfusion Injury

Authors: Tao Wang, Guodong Wu, Peigen Gao, Fenghui Zhuang, Zeyu Wang, Ziheng Zhou, Chongwu Li, Junqi Wu, Deping Zhao

💡 Key Finding

Inhaled MSC-EVs significantly ameliorate lung ischemia-reperfusion injury, showing superior efficacy compared to intravenous delivery.

Background: Lung ischemia–reperfusion injury (IRI) is a major contributor to primary graft dysfunction (PGD) after lung transplantation. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as promising therapeutic agents in inflammatory diseases by ameliorating tissue damage and promoting repair. However, the anti-inflammatory efficacy of these approaches and the underlying mechanisms in lung ischemia–reperfusion injury remain incompletely understood. Methods: The protective effects of mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) against lung ischemia–reperfusion injury were evaluated using two delivery approaches, inhalation and intravenous injection. Both in vivo and in vitro models were employed to assess the biological activity of MSC-EVs and to elucidate the underlying molecular mechanisms. In addition, a rat orthotopic lung transplantation (OLT) model was established to further examine the translational relevance of MSC-EVs. Results: MSC–EVs treatment significantly ameliorated lung IRI, with inhalation showing superior efficacy over intravenous delivery. Mechanistically, miR-22-3p within MSC-EVs targeted macrophage NLRP3, suppressing activation of the NLRP3/Caspase-1/IL-1β pathway and promoting M2 polarization. The protective efficacy was confirmed in a clinically relevant rat OLT model, underscoring their translational potential. Conclusions: Our findings indicate that inhaled MSC-derived extracellular vesicles attenuate lung ischemia–reperfusion injury by promoting macrophage polarization via the miR-22-3p/NLRP3/IL-1β pathway, supporting their potential as a cell-free therapeutic approach to mitigate primary graft dysfunction after lung transplantation.

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Hypoxia-conditioned BMSC exosomes improve short-term spinal cord injury outcomes via the miR-615-3p/PDE4C-mediated cAMP/PKA pathway
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-04895-9

Hypoxia-conditioned BMSC exosomes improve short-term spinal cord injury outcomes via the miR-615-3p/PDE4C-mediated cAMP/PKA pathway

Authors: Wei Bian, Xiangyu Zeng, Ziwen Liu, Mingyan Guan, Tegeleqi Bu, Haoze Li, Zewei Gao, Jianyu Liu

💡 Key Finding

Hypoxic preconditioning enriches miR-615-3p in BMSC-derived exosomes, enhancing their neuroprotective potential.

Spinal cord injury (SCI) remains a significant global health challenge with limited effective therapeutic options. Exosomes derived from mesenchymal stem cells (MSCs) have emerged as promising neuroprotective agents due to their biocompatibility and immunomodulatory properties. This study investigated the therapeutic potential of hypoxia-conditioned bone marrow MSC (BMSC)-derived exosomes in both in vitro and in vivo SCI models. Hypoxic preconditioning significantly enriched miR-615-3p in BMSC-derived exosomes. In spinal neuron injury models, hypoxic exosomes enhanced cell viability, reduced apoptosis, and ameliorated dysfunction of the mitochondria-associated endoplasmic reticulum membranes (MAMs). Mechanistically, miR-615-3p directly targeted and suppressed phosphodiesterase 4C (PDE4C), activating the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway. This in turn modulated calcium signaling, attenuated mitochondrial calcium overload, and reduced endoplasmic reticulum stress (ERS). In a mouse model of SCI, short-term treatment with hypoxic exosomes promoted functional recovery within a 14-day post-injury period, as evidenced by improved locomotor performance, reduced lesion volume, attenuated tissue edema, and decreased inflammatory cell infiltration. Furthermore, in vivo administration of hypoxic exosomes upregulated miR-615-3p and downregulated PDE4C expression in injured spinal cord tissues. These results demonstrate that hypoxia-conditioned BMSC-derived exosomes exert neuroprotective effects via the miR-615-3p/PDE4C axis, highlighting their potential as a novel therapeutic strategy for SCI by targeting calcium homeostasis and mitochondrial-ER dysfunction. These findings demonstrate the short-term therapeutic potential of hypoxia-conditioned exosomes in SCI. However, further preclinical studies, including long-term follow-up to assess the durability of recovery and potential late-onset effects, alongside clinical validation, are warranted before clinical translation.

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Therapeutic potential of mesenchymal stromal cells in COVID-19: a meta-analysis of clinical trials conducted since the pandemic onset
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-05020-6

Therapeutic potential of mesenchymal stromal cells in COVID-19: a meta-analysis of clinical trials conducted since the pandemic onset

Authors: Meng-Qi Yuan, Yue-Fei Pan, Zi-Ying Zhang, Ya-Xin Wu, Kai-Di Zhu, Ze-Rui Wang, Ze-Yi Zhang, Jia-Qi Xiong, Zhe Xu, Lei Huang, Fu-Sheng Wang, Lei Shi

💡 Key Finding

MSC therapy significantly reduced all-cause mortality in severe/critical COVID-19 patients (OR=0.74, 95% CI 0.55–0.99) with low heterogeneity and no publication bias.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can induce immune dysregulation and multi-organ injury; mesenchymal stromal cell (MSC) therapy has shown promise in clinical trials for COVID-19 and may have broader applicability to pneumonia induced by respiratory viruses (e.g., the influenza virus). This meta-analysis synthesized the available comparative clinical evidence on the safety and efficacy of MSCs in patients with moderate to critical COVID-19 and examined the reported outcomes relevant to Long-COVID. Methods: We searched the PubMed, Embase, and CNKI databases for original, comparative studies in moderate, severe, or critical COVID-19 published up to September 2, 2024. Twenty-four eligible studies (13 RCTs and 11 non-randomized controlled trials; n=1080) were included in the mortality meta-analysis. Patients were assigned to either the intervention group (MSC therapy plus standard care) or the control group (standard care with or without placebo). The primary efficacy outcome was all-cause mortality, while the primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs). Secondary outcomes included clinical recovery, hospitalization metrics, chest imaging, and inflammatory biomarkers. We performed a pooled meta-analysis on mortality with subgroup analyses (by disease severity, administration route, dosing frequency, and study design), assessment of publication bias (using funnel plots and Egger's test), and evaluation of the quality of evidence via the GRADE approach. AEs/SAEs were analyzed using meta-analysis and descriptive statistics, while other secondary outcomes were summarized descriptively. Results: MSC therapy significantly reduced all-cause mortality (MSC: 26.4% vs control: 31.9%; fixed-effect OR=0.74, 95% CI 0.55–0.99), with low heterogeneity (I2=2.8%, P=0.422[Q-test]) and no publication bias. The quality of evidence was moderate (according to the GRADE assessment). The subgroup analysis revealed a significant survival benefit in severe/critical patients (OR=0.73, 95% CI 0.54–0.98) but not in studies that included moderate cases (OR=0.91, 95% CI 0.23–3.65). No significant heterogeneity was found across study designs, administration routes, or dosing frequencies, which confirmed the robustness of the primary findings while indicating insufficient evidence to determine the optimal regimen. The secondary outcomes suggested improvements in clinical recovery, pulmonary function, and pro-/anti-inflammatory cytokine balance in patients that received MSC therapy. Limited studies with long-term follow-up indicated potential benefits for Long-COVID outcomes (e.g., fatigue, quality of life, residual CT abnormalities, and exercise tolerance). No significant differences were observed in AEs or SAEs post-MSC infusion, which suggested that MSC therapy was well tolerated. Conclusion: This meta-analysis indicated that MSC therapy may reduce mortality in patients with severe or critical COVID-19, demonstrating a favorable safety profile and potential benefits for Long-COVID and other viral pneumonias. Further large-scale, rigorous RCTs and mechanistic studies are warranted to strengthen the evidence base and standardize MSC administration regimens (source, dosing, frequency).

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Bone Marrow-Derived Mesenchymal Stem Cells Alleviate Hepatic Lipid Metabolism Disorders After Scald Injury: Integrating Liver Transcriptome and Metabolome
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-025-04774-9

Bone Marrow-Derived Mesenchymal Stem Cells Alleviate Hepatic Lipid Metabolism Disorders After Scald Injury: Integrating Liver Transcriptome and Metabolome

Authors: Zhian Chen, Ya'e Yang, Xiangwen Shi, Rensheng Yang, Wei Fang, Guangjin Liang, Yun Li, Jing Gao, Lihua Ma, Junchun Yang, Rongqing Pang

💡 Key Finding

Portal vein infusion of BMSCs significantly ameliorates scald-induced hepatic lipid metabolism disorders in rats, improving body weight recovery and reducing hepatic lipid accumulation.

Previous studies have confirmed that scald injuries can lead to disturbances in hepatic lipid metabolism, and bone marrow-derived mesenchymal stem cells (BMSCs) have emerged as a promising therapeutic strategy for alleviating such disorders. However, research focusing on the regulation and restoration of liver lipid metabolic processes remains limited. In this study, we investigated the effects of BMSCs on hepatic lipid metabolism disorders induced by scald injury in rats through integrated transcriptomic and metabolomic analyses. The results demonstrated that portal vein infusion of BMSCs markedly improved body weight recovery, reduced hepatic lipid accumulation, normalized serum lipid profiles, and attenuated liver injury following scalding. Combined transcriptomic and metabolomic data further suggested that the therapeutic mechanism may involve inhibition of NF-κB/Gadd45a signaling in hepatocytes, restoration of sphingolipid metabolism, enhancement of hepatic lipid conversion, and suppression of adipocyte lipolysis. Overall, this study provides a theoretical basis for the potential clinical application of BMSCs in treating hepatic lipid metabolism disorders secondary to severe burn injury.

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Fndc5 modification optimizes the therapeutic effect of rat MSCs on sepsis-induced ALI/ARDS via activating the PI3K/AKT signaling pathway
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-04903-y

Fndc5 modification optimizes the therapeutic effect of rat MSCs on sepsis-induced ALI/ARDS via activating the PI3K/AKT signaling pathway

Authors: Yuling Luo, Minhua Li, Shan Lin, Zheng Gong, Sumei Wang, Ziqing Zhou, Shiyue Li

💡 Key Finding

Fndc5 overexpression enhances MSC retention in injured lungs and augments their proliferation and migration in vitro.

Background: Acute lung injury/Acute respiratory distress syndrome (ALI/ARDS) is a life-threatening inflammatory lung disorder characterized by high mortality rates and a lack of effective treatment options. Although mesenchymal stem cell (MSC)-based therapies have emerged as a promising approach for ARDS management, optimizing their therapeutic efficacy remains a significant challenge. Recent advances in gene modification techniques have opened new avenues for enhancing MSC functionality. Among these, Fibronectin type III domain-containing protein 5 (Fndc5)/irisin has attracted considerable attention due to its ability to improve endothelial function. This study aims to evaluate the therapeutic potential of Fndc5-modified MSCs in sepsis-induced ALI/ARDS and to elucidate the underlying molecular mechanisms driving their protective effects. Methods: To comprehensively evaluate the therapeutic potential of Fndc5-modified MSCs (MSCs-Fndc5) in ARDS, we employed both in vivo and in vitro experimental models. In vivo, a mouse model of sepsis-induced ALI was established through intraperitoneal injection of lipopolysaccharide (LPS), and the protective effects of MSCs-Fndc5 were systematically assessed by analyzing lung histopathology, inflammatory cytokine levels, vascular endothelial integrity, lung wet-to-dry weight ratio, and MSC retention in lung tissue. In parallel, in vitro studies were conducted to investigate the role of MSCs-Fndc5 in mitigating LPS-induced endothelial cell (EC) injury, with a focus on EC proliferation, angiogenesis, barrier permeability, apoptosis, and the regulation of key signaling pathways. Results: Fndc5 modification significantly increased the retention rate of MSCs in sepsis-induced ALI murine model while augmenting their in vitro proliferation and migration potential. In vivo, treatment with Fndc5-modified MSCs markedly attenuated lung inflammation, as evidenced by reduced levels of pro-inflammatory cytokines, decreased neutrophil infiltration, and improved lung histopathology. Additionally, MSCs-Fndc5 alleviated pulmonary edema, reduced fibrosis, lowered the lung wet-to-dry weight ratio, and preserved vascular endothelial integrity. In vitro, MSCs-Fndc5 significantly enhanced cell proliferation, migration, angiogenesis, endothelial barrier function, apoptosis inhibition, likely via PI3K/AKT pathway activation. Conclusions: Fndc5 overexpression in MSCs augments their therapeutic efficacy in sepsis-induced ALI/ARDS, which may be achieved by activating the endothelial PI3K/AKT pathway and improving MSCs retention in vivo. These findings propose MSCs-Fndc5 as a promising therapeutic strategy for sepsis-induced ALI/ARDS by enhancing endothelial repair, curbing inflammation, and modulating pivotal signaling pathways.

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Mesenchymal stem cell-derived extracellular vesicles in the treatment of type 2 diabetes and its complications: current progress and future directions
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-04991-w

Mesenchymal stem cell-derived extracellular vesicles in the treatment of type 2 diabetes and its complications: current progress and future directions

Authors: Sha Zhang, Zong-Yu Zhang, Ruo-Nan Tang, Kai Zhang, Yu Fu, Hua Tian, Jing Ma, Yan Jin, Chen-Xi Zheng, Bing-Dong Sui

💡 Key Finding

MSC-EVs show therapeutic potential in T2D by modulating inflammation, promoting tissue regeneration, and improving insulin resistance.

Type 2 diabetes (T2D) and its complications represent a complex disorder involving multiple pathophysiological processes. Although conventional therapeutic approaches partially regulate blood glucose, they fail to fundamentally reverse disease progression or effectively prevent complications. This review summarizes the current research advance and challenges of using different forms of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) in treating T2D and complications. It begins with an introduction to the characteristics of MSC-EVs. Subsequently, the mechanisms and therapeutic prospects of natural MSC-EVs are analyzed, with a focus on their roles in inflammatory modulation, tissue regeneration, and improving insulin resistance. Engineering MSC-EVs, covering strategies including optimizing MSC culture conditions, modifying EV contents, and establishing MSC-EV delivery systems based on bioactive materials are then discussed, which boost EV yield and quality while enhancing therapeutic efficacy. Current challenges, including the limited yield and high heterogeneity of natural MSC-EVs, as well as issues related to long-term safety, immunocompatibility, and large-scale production of engineered MSC-EVs are finally overviewed, with emphasizing artificial intelligence in guiding future research directions. These summaries are crucial for clinical translation of MSC-EVs and will ultimately provide T2D patients with an effective and safe treatment option.

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Extracorporeal cardiac shock wave stimulation enhances the therapeutic efficacy of intravenously delivered endothelial colony-forming cells via PI3K/AKT signaling in a rat myocardial infarction model
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-04913-w

Extracorporeal cardiac shock wave stimulation enhances the therapeutic efficacy of intravenously delivered endothelial colony-forming cells via PI3K/AKT signaling in a rat myocardial infarction model

Authors: Mingqiang Wang, Dan Yang, Yiming Ma, Yunke Shi, Jinping Lun, Chaoyue Zhang, Xinbin Li, Yuchen Shi, Hongyan Cai

💡 Key Finding

ECSW preconditioning enhances ECFC function in vitro, including migration, tube formation, proliferation, and VEGF-A secretion, while reducing apoptosis, via PI3K/AKT activation.

Background: Extracorporeal cardiac shock wave (ECSW) therapy enhances the function of endothelial colony-forming cells (ECFCs), but whether it can serve as a preconditioning strategy to enhance myocardial infarction (MI) therapy remains unclear. This study investigated the efficacy and mechanism of intravenously delivered ECSW-preconditioned ECFCs (SW-ECFCs) in a rat MI model. Methods: ECFCs were isolated from the bone marrow of ApoE-/- rats and fully characterized. RNA sequencing of control ECFCs versus SW-ECFCs revealed significant enrichment of the PI3K/AKT pathway. We therefore performed a series of in vitro functional assays on these cells, including Transwell migration, Matrigel tube formation, CCK-8 proliferation, flow cytometric apoptosis analysis, and VEGF-A ELISA. The role of the PI3K/AKT pathway was interrogated using the inhibitor LY294002. Subsequently, an acute MI model was established in ApoE-/- rats via left anterior descending coronary artery ligation. Rats were randomized into four groups: MI+PBS, MI+ECFCs, MI+SW-ECFCs, and MI+LY294002-pretreated SW-ECFCs (LY-SW-ECFCs), with sham-operated rats as controls. Comprehensive evaluations included echocardiography, serum injury biomarkers, TTC, and histopathological (H&E, Masson) staining, immunohistochemical detection of cardiomyocyte apoptosis and p-eNOS, immunofluorescence assessment of ECFC homing and vascular markers (CD31, α-SMA, VEGF-A), tissue/plasma nitric oxide measurement, and Western blot analysis of PI3K/AKT signaling proteins. Results: Transcriptomic analysis revealed significant enrichment of the PI3K/AKT pathway in SW-ECFCs. Functionally, ECSW enhanced ECFCs migration, tube formation, proliferation, and VEGF-A secretion, while reducing apoptosis; these effects were largely abolished by PI3K inhibition. In vivo, serum levels of CK, CK-MB, and LDH were significantly elevated in all MI groups compared to the Sham group (P<0.01), indicating comparable initial injury. However, no significant differences were observed among treatment groups (P>0.05). SW-ECFCs transplantation significantly improved cardiac function, reduced infarct size, fibrosis, and apoptosis, and enhanced angiogenesis (P<0.05). These benefits were associated with increased levels of p-AKT, p-eNOS, and BCL-2 protein as well as nitric oxide content, while suppressing the expression of cleaved caspase-3 (P<0.05). Crucially, all these therapeutic benefits were largely abolished by PI3K inhibition. Conclusion: In conclusion, this study demonstrates that preconditioning ECFCs with ECSW significantly enhances their therapeutic efficacy for myocardial infarction, improving both cardiac function and structural repair. These benefits are mediated primarily through activation of the PI3K/AKT signaling pathway, which augments cell homing, paracrine activity, and survival, thereby providing a novel and promising strategy for cardiac regeneration.

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DMOG Pretreatment Restores Osteogenic–Adipogenic Balance and Mitochondrial Function in ONFH BMSCs through the HIF-1α/Homer3 Pathway
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-05026-0

DMOG Pretreatment Restores Osteogenic–Adipogenic Balance and Mitochondrial Function in ONFH BMSCs through the HIF-1α/Homer3 Pathway

Authors: Qiheng Chen, Lingxian Yi, Penghui Nie, Jie Wang, Jing Zhu, Jiang Peng, Tujun Weng

💡 Key Finding

DMOG pretreatment restores osteogenic–adipogenic balance in ONFH-derived BMSCs by stabilizing HIF-1α.

Background: Osteonecrosis of the femoral head (ONFH) is a progressive orthopedic disorder that often culminates in femoral head collapse and joint failure. Dysfunction of bone marrow mesenchymal stem cells (BMSCs), including impaired osteogenesis, enhanced adipogenesis, and mitochondrial dysfunction, has been increasingly recognized as a central driver of ONFH pathogenesis. However, the molecular mechanisms linking metabolic stress to lineage imbalance remain poorly defined. Methods: Paired BMSCs were isolated from necrotic femoral head regions (fhBMSCs) and the iliac crest (iBMSCs) of ONFH patients. Functional assays, RNA sequencing, and molecular analyses were performed to evaluate the effects of the hypoxia mimetic dimethyloxalylglycine (DMOG) on osteogenic–adipogenic balance, mitochondrial function, and senescence. Loss-of-function experiments targeting hypoxia-inducible factor-1α (HIF-1α) and Homer3 were conducted to elucidate mechanistic pathways. Results: Compared with iBMSCs, fhBMSCs exhibited impaired osteogenesis, enhanced adipogenesis, mitochondrial dysfunction, and increased senescence. DMOG pretreatment restored osteogenic differentiation, suppressed adipogenesis, improved mitochondrial dynamics, reduced oxidative stress, and enhanced bioenergetic metabolism. These protective effects were dependent on HIF-1α stabilization. Transcriptomic profiling identified Homer3 as a downstream negative regulator of HIF-1α. Homer3 was aberrantly upregulated in fhBMSCs but suppressed by DMOG, and its knockdown mimicked the effects of DMOG by promoting osteogenesis, inhibiting adipogenesis, enhancing mitophagy, and restoring mitochondrial function. Conversely, silencing HIF-1α abolished DMOG-mediated benefits and reinstated Homer3 expression. Conclusions: This study identifies the HIF-1α/Homer3 axis as a central regulator of lineage balance and mitochondrial homeostasis in ONFH-derived BMSCs. Pharmacological targeting of this pathway with DMOG or related prolyl hydroxylase inhibitors may provide a promising joint-preserving therapeutic strategy for ONFH.

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Generation of biologically responsive colon-like intestinal tissue patches from human induced pluripotent stem cells using a rapid co-differentiation platform
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-05006-4

Generation of biologically responsive colon-like intestinal tissue patches from human induced pluripotent stem cells using a rapid co-differentiation platform

Authors: William Dalleywater, Alexander V. Predeus, Batuhan Cakir, Pavel Mazin, Jayakumar Vadakekolathu, Sergio Rutella, Marian L. Meakin, Alison A. Ritchie, Shamir Montazid, Sara Cuevas Ocaña, Nadine Holmes, Victoria Wright, Fei Sang, Silvia Santoni, Adam Bills, Declan Sculthorpe, Rasa Elmentaite, Sarah A. Teichmann, Shazia Irshad, Ian Tomlinson, Andrew Silver, Ricky D. Wildman, Nicholas R. F. Hannan, Felicity R. A. J. Rose, Mohammad Ilyas

💡 Key Finding

Developed a rapid (8-day) serum-free co-differentiation protocol for hiPSCs to generate multiple intestinal cell lineages (epithelial, mesenchymal, endothelial) simultaneously.

The intestinal mucosa is a complex functional layer formed from diverse cell types including epithelial cells within crypts and villi and an array of mesenchymal cells. Many intestinal diseases involve loss of the surface mucosa, which is difficult to restore and delays healing. We hypothesized that a transplantable intestinal mucosal tissue graft could aid healing. To create such a graft, we developed a novel early-stage human induced pluripotent stem cell (hiPSC) co-differentiation platform capable of generating multiple intestinal cell lineages (epithelial, mesenchymal, and endothelial) in 8 days. This protocol is simple, serum-free, and reduces animal product use. We confirmed cell identity via RNA and protein expression profiles typical of intestinal lineages. Using bulk and single-cell RNA sequencing, we characterized global transcriptional profiles, showing intestinal identity with early colonic polarization. Results were replicated across multiple hiPSC lines and an independent center. Culturing derived cells on collagen hydrogels formed colon-like intestinal patches (CL-IPs). Upon transplantation into mouse subcutis, CL-IPs developed into colon-like tissue structures including crypts, stromal and muscle layers, and human-origin vasculature that anastomosed with murine vasculature. Teratoma assays and molecular analyses showed no residual pluripotency. This platform shows potential for intestinal mucosal regeneration therapy and as a physiologically relevant in vitro model of intestinal pathobiology.

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A single-donor proof-of-concept single-cell analysis maps heterogeneous differentiation trajectories toward cartilage-like states in human urine-derived stem cells
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-05223-x

A single-donor proof-of-concept single-cell analysis maps heterogeneous differentiation trajectories toward cartilage-like states in human urine-derived stem cells

Authors: Alexander Schulz, Emily M. Brockmann, Miriam Zentgraf, Andreas S. Baur, Steffen Uebe, Arif B. Ekici, Mark Dedden, Sebastian Zundler, Christian T. Thiel

💡 Key Finding

Single-cell RNA sequencing of urine-derived stem cells (USCs) reveals heterogeneous differentiation trajectories toward cartilage-like states, with only a minority of cells achieving confident transcriptional similarity to mature cartilage.

Background: Urine-derived stem cells (USCs) represent an accessible and non-invasive cell source with reported chondrogenic differentiation potential. However, the cellular heterogeneity and transcriptional dynamics underlying USC differentiation remain incompletely understood, limiting their translational interpretation. Methods: We combined functional differentiation assays with single-cell RNA sequencing to characterize USC differentiation at both phenotypic and transcriptional levels. Chondrogenic and osteogenic differentiation were assessed using histological staining, quantitative PCR, and three-dimensional spheroid cultures. Single-cell transcriptomic analysis was performed on integrated datasets of undifferentiated and differentiated USCs, followed by pseudotime trajectory inference and mapping to a human cartilage reference atlas. Results: Chondrogenic induction resulted in reproducible acquisition of cartilage-associated features, including glycosaminoglycan-rich extracellular matrix deposition, increased expression of SOX9, and formation of aggrecan-positive spheroids. In this donor, single-cell analysis mapped an inferred differentiation trajectory from proliferative states towards differentiated populations, although the fine-grained pseudotemporal ordering was sensitive to analytical choices and is therefore interpreted qualitatively. Along this inferred trajectory, we identified a candidate transient transcriptional state associated with elevated CDH1 expression and epithelial-like aggregation features. Probabilistic mapping to a human cartilage reference atlas indicated that overall mapping confidence was low (median prediction score 0.34) and that only a minority of cells showed confident transcriptional similarity (prediction score ≥0.5) to mature/articular cartilage-associated reference states (7.8% of all cells and 17.6% of chondrogenically induced cells). This confident similarity was concentrated in a few clusters at the differentiated end of the trajectory rather than representing the bulk of the culture, and label-transfer confidence was not equated with chondrocyte identity. Despite this enrichment, differentiated populations exhibited transcriptional heterogeneity, including subsets of cells associated with hypertrophic, fibrocartilage-like, and contractile gene programmes, indicating the presence of multiple differentiation trajectories. Conclusions: This single-donor proof-of-concept study suggests that USC differentiation may involve a candidate transient, aggregation-associated transcriptional state accompanied by CDH1 expression and gives rise to heterogeneous lineage-associated outcomes, with only a minority of cells acquiring confident transcriptional similarity to mature cartilage. Because these observations derive from one donor, they should be interpreted as hypothesis-generating and require validation across independent donors before donor-independent or translational conclusions for cartilage regeneration can be drawn. These findings nonetheless provide a single-cell resolution framework for future multi-donor validation of USC differentiation and its inherent transcriptional heterogeneity.

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Emerging roles of the long non-coding RNAs MALAT1 and TUG1 during differentiation of adipose tissue-derived mesenchymal stem cells towards insulin-producing cells
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-05125-y

Emerging roles of the long non-coding RNAs MALAT1 and TUG1 during differentiation of adipose tissue-derived mesenchymal stem cells towards insulin-producing cells

Authors: Eman F. Sanad, Alaa Ahmed Saad, Joy Rafeek, Rana Mokbel, Mayar Abdallah, Nadeen Emad, Hagar Adel Mohamed, Yasmin Alaa, Yumna Medhat Mahmoud, Dina H. Kassem

💡 Key Finding

MALAT1 and TUG1 expression levels significantly increase during differentiation of adipose tissue-derived mesenchymal stem cells (Ad-MSCs) into insulin-producing cells (IPCs).

Background: Generation of insulin-producing cells (IPCs) from stem cells provides great hope for patients with diabetes mellitus (DM). Long non-coding RNAs (lncRNAs) ignited much interest regarding their role in determining the fate of stem cells. The lncRNAs MALAT1 and TUG1 have been reported to be interrelated with β-cell dysfunction and/or DM. However, their role during generation of IPCs from stem cells has not been adequately studied. Thus, the current study aimed to investigate the role of MALAT1 and TUG1 during differentiation of adipose tissue-derived mesenchymal stem cells (Ad-MSCs) towards IPCs. Methods: Ad-MSCs were isolated from rat epididymal fat pads, characterized and induced to differentiate towards IPCs. Assessment of differentiation was done by measuring expression levels of various β-cell-related markers using RT-qPCR, as well as morphological changes, and dithizone staining. Expression levels of MALAT1 and TUG1 were also measured by RT-qPCR. Several in-silico analyses were done using RNA–protein Association and Interaction Networks (RAIN) database. Results: MALAT1 and TUG1 expression levels were significantly increased during differentiation of Ad-MSCs into IPCs as compared to control uninduced cells. Furthermore, generated networks from RAIN database revealed an interplay between MALAT1 and TUG1, and between each of them with several common targets like GAS5, HOTAIR and TP53COR1. Conclusions: The current study portrays MALAT1 and TUG1 as novel interrelated molecular mediators and important regulatory nodes enhancing differentiation of Ad-MSCs towards IPCs. Their upregulation during differentiation can be interrelated with competitive endogenous RNA (ceRNA) networks, mediating various epigenetic modifications, orchestrating signaling pathways and overcoming cellular stress during reprogramming/differentiation.

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Cadherin 19 deficiency inhibits osteogenic differentiation and bone formation by regulating PI3K/AKT signaling pathway
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-05061-x

Cadherin 19 deficiency inhibits osteogenic differentiation and bone formation by regulating PI3K/AKT signaling pathway

Authors: Huan Zhou, Yizhao Cheng, Liangxing Chen, Yaqin Zhang, Huimin Xiao, Chenhui Zhou, Hui Fu, Xiaoyan Zhang, Liangliang Xu, Daohua Xu

💡 Key Finding

CDH19 deficiency impairs osteoblast proliferation and differentiation, leading to reduced bone mass and microstructural deterioration.

Background: Osteoporosis (OP) is a systemic bone disease characterized by damage to bone strength, leading to increased bone fragility and fracture risk. Cadherin 19 (CDH19) is located on chromosomes 18q22-q23, and 18q deletion is associated with terminal deletion diseases, including foot/hand deformities. However, the role of CDH19 in bone remains undefined. Methods: A conditional knockout mouse model of the CDH19 gene was constructed using the Cre-loxP system, and the bone mass and bone morphology in mice were investigated using microCT and histological staining. Osteoblasts were isolated and cultured from wild-type and CDH19 knockout mice. Cell proliferation and differentiation were explored through EdU labeling, qPCR, alkaline phosphatase (ALP)/ alizarin red S (ARS) staining, and Western blot assays. The expression of genes altered in CDH19 gene knockout osteoblast was checked by RNA sequencing (RNA-seq), and subsequently confirmed by immunofluorescence and Western blot. Results: We found that CDH19 could maintain the normal proliferation and differentiation in osteoblasts. After knocking out the CDH19 gene, the abilities of proliferation and osteogenesis were significantly inhibited in osteoblasts. Moreover, the bone mass of CDH19 knockout mice was significantly reduced, characterized by decreases in bone density, trabecular number, and bone volume fraction. The RNAseq analysis and western blot showed the PI3K/AKT signaling pathway was significantly inhibited in osteoblasts with CDH19 deletion. Furthermore, we demonstrated that administration of PI3K/AKT signaling pathway agonist 740Y-P partially alleviated the inhibition of osteogenic differentiation caused by CDH19 deletion in vitro and in vivo. Conclusion: This study demonstrated that CDH19 regulated osteogenic differentiation by modulating the PI3K/AKT signaling pathway in osteoblasts. CDH19 may become a novel target for the treatment of bone diseases.

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An Open Phase I/IIa Study Evaluating Safety, Patient-Reported Outcomes, and Voice Function After Surgery, Local Administration of Mesenchymal Stromal Cells, and Voice Training in Patients with Vocal Fold Scarring and Dysphonia
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-05022-4

An Open Phase I/IIa Study Evaluating Safety, Patient-Reported Outcomes, and Voice Function After Surgery, Local Administration of Mesenchymal Stromal Cells, and Voice Training in Patients with Vocal Fold Scarring and Dysphonia

Authors: Erika Bergström Börlin, Ulrika Nygren, Maria Södersten, Svante Granqvist, Nadir Kadri, Ida Rasmusson Duprez, Katarina Le Blanc, Stellan Hertegård

💡 Key Finding

Local injection of autologous bone marrow-derived MSCs combined with voice training was safe with no treatment-related side effects over 36 months.

Background: Damage to the vocal folds can result in scarring, leading to chronic, severe voice impairments for which lasting and effective treatments are currently lacking. The aim of this clinical trial was to evaluate the safety and effectiveness of autologous bone marrow-derived Mesenchymal Stromal Cell (MSC) therapy for patients with vocal fold scarring and severe dysphonia. Additionally, the study sought to propose a post-operative voice training protocol and explore its potential role in facilitating voice improvement. Methods: Eight patients with vocal fold scarring and chronic dysphonia underwent surgical scar resection and autologous MSC injection, followed by voice training. Safety was continuously monitored for up to 36 months postoperatively. Data to evaluate therapeutic efficacy was collected pre-treatment, 3 and 12 months post-treatment. Assessments included analysis of vocal fold vibrations, Phonation Threshold Pressure, and Maximum Phonation Time. Patient-reported measures were collected using the Voice Handicap Index, the Vocal Fatigue Index, and ratings of major symptoms and their impact on daily life. Treatment effectiveness was analyzed at both group and individual levels, with clinically relevant changes predefined. Results: No treatment-related side effects were reported within the 36 months of follow-up. Group-level analysis of the self-reported outcomes indicated positive treatment effects, with Voice Handicap Index scores reduced by −25.9 points (95% CI [−48, −3.6]) between pre-treatment and 12 months post-treatment. Group-level aerodynamic changes were small with Phonation Threshold Pressure showing a marginal positive change on average (−0.94 cmH₂O), as did Maximum Phonation Time (+0.2 s). At the individual level, clinically relevant improvements were observed in 63–88% of patients depending on the parameter analyzed. Three patients (38%) achieved relevant improvement on ≥5/6 selected parameters in combination. All participants in voice training reported reduced vocal strain following training. Conclusions: This preliminary, uncontrolled study indicates that local administration of autologous bone marrow-derived MSCs appears safe and is associated with clinically relevant patient-reported outcome improvements in a majority of patients. Larger, controlled trials are needed in the future to establish efficacy and possibly disentangle contributions of MSCs versus voice training. Trial registration: This clinical trial is registered in ClinicalTrials.gov (NCT04290182).

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Innovative strategies for immune thrombocytopenia treatment: immunomodulatory mechanisms and clinical potential of mesenchymal stem cells
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-05000-w

Innovative strategies for immune thrombocytopenia treatment: immunomodulatory mechanisms and clinical potential of mesenchymal stem cells

Authors: Xin Zhou, Ningning Shan

💡 Key Finding

MSCs offer a dual therapeutic role in ITP by modulating immune responses and repairing the bone marrow niche, addressing both platelet destruction and production.

Immune thrombocytopenia (ITP) is a heterogeneous autoimmune disorder characterized by increased platelet destruction and impaired megakaryopoiesis within a dysregulated bone marrow niche. Conventional therapies often achieve only transient platelet recovery, failing to restore immune tolerance, thereby underscoring the need for mechanism-based therapeutic strategies. Mesenchymal stem cells (MSCs) have emerged as promising candidates due to their ability to modulate immune responses and repair the hematopoietic microenvironment. This review synthesizes current evidence regarding the biological properties, immunomodulatory mechanisms, and therapeutic applications of MSCs in ITP, emphasizing intrinsic abnormalities of patient-derived MSCs and the corrective potential of exogenous MSCs from distinct tissue sources. It further integrates emerging insights into MSC functional heterogeneity, optimization of culture conditions, priming strategies, and cellular engineering approaches that may enhance therapeutic efficacy and safety. By highlighting the interplay between immune tolerance restoration and bone marrow niche remodeling, this review provides a translational framework that links mechanistic understanding to the future clinical development of MSC-based therapies for ITP.

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Hybrid endometrial-derived hydrogel and human endometrial organoids synergize for uterine regeneration in an immunocompetent murine model
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-04900-1

Hybrid endometrial-derived hydrogel and human endometrial organoids synergize for uterine regeneration in an immunocompetent murine model

Authors: María Gómez-Álvarez, Clara Bueno-Fernandez, Emilio Francés-Herrero, Marcos Agustina-Hernández, Paula Alonso-Frías, Nadaya Corpas, Amparo Faus, Ana Díaz, Antonio Pellicer, Hortensia Ferrero, Irene Cervelló

💡 Key Finding

A hybrid hydrogel combining PuraMatrix® and endometrial extracellular matrix (EndoECM) provides a biocompatible and mechanically stable scaffold for human endometrial organoid delivery in vivo.

Background: The human endometrium is a regenerative tissue essential for fertility, but pathological conditions like Asherman syndrome, endometrial atrophy, and thin endometrium can impair its function. Current therapies lack efficacy, driving demand for innovative regenerative therapies. In this context, endometrial-derived hydrogels and organoids have shown promise individually for tissue regeneration, but their combined therapeutic potential has not been previously evaluated in vivo. This study explores a dual regenerative strategy combining a hybrid hydrogel — composed of synthetic PuraMatrix® and endometrial extracellular matrix hydrogel — with human endometrial organoids in an immunocompetent murine model with uterine damage. Methods: Endometrial damage model was established in female C57BL/6 mice (n=46) via uterine injury using 70° ethanol. After 4 days of endometrial damage, human endometrial organoids were co-injected with the hybrid hydrogel into the uterine horns. Two weeks post-injection, a subset of mice (n=25) was sacrificed for biocompatibility, histological, and transcriptomic analyses. Functional recovery of the endometrium was assessed in the remaining animals (n=21) through fertility outcome evaluation. For endometrial regeneration analyses, normally distributed data were analyzed by one-way ANOVA and Tukey’s multiple comparisons, while non-normally distributed data were analyzed by the Kruskal–Wallis test with Dunn’s multiple comparisons. For fertility outcomes, t-test or Mann–Whitney U tests for 2-by-2 comparisons were performed. Results: Histological and molecular analyses revealed that the therapy improved endometrial thickness, gland density, and vascularization, and reduced fibrosis and ferroptosis, aligning tissue characteristics closer to healthy controls. However, fertility outcomes were not fully restored, potentially due to the persistence of the synthetic component of the hybrid hydrogel. Thus, further studies are needed to confirm complete hydrogel resorption and its impact on fertility restoration. Conclusions: In conclusion, this study demonstrates the biocompatibility and regenerative potential of human endometrial organoids combined with a hybrid hydrogel for uterine regeneration, offering a promising avenue for treating endometrial pathologies.

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Editorial Expression of Concern: Co-encapsulation of HNF4α overexpressing UMSCs and human primary hepatocytes ameliorates mouse acute liver failure
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-04962-1

Editorial Expression of Concern: Co-encapsulation of HNF4α overexpressing UMSCs and human primary hepatocytes ameliorates mouse acute liver failure

Authors: Defu Kong, Huiming Xu, Mo Chen, Yeping Yu, Yongbing Qian, Tian Qin, Ying Tong, Qiang Xia, Hualian Hang

💡 Key Finding

An Editorial Expression of Concern has been issued regarding the reporting of animal ethics approval in the original article.

The Editor-in-Chief is issuing an Editorial Expression of Concern to alert readers about concerns regarding the reporting of animal ethics approval in this article. The article cites approval number SYXK 2008 0050, which was noted to appear in multiple publications describing different experiments. The authors have explained that this number refers to an Experimental Animal Use License for the animal facility rather than a study specific ethics approval and have provided documentation indicating that separate ethical approval was obtained for this study. Despite this, the reporting of animal use approval in the article and the use of a general approval instead of a specific one is inadequate. Readers are therefore advised to interpret the information regarding animal ethics approval with caution.

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FHOD3 deficiency disrupts sarcomere organization and activates CaMKII signaling in human stem cell-derived cardiomyocytes
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-04902-z

FHOD3 deficiency disrupts sarcomere organization and activates CaMKII signaling in human stem cell-derived cardiomyocytes

Authors: Mingyu Wei, Xiaojie Hou, Siyao Zhang, Xianjing Hu, Xi Chen, Zhen Gao, Shuwan Xu, Zhan Shi, Min Zhu, Feng Lan, Ming Cui

💡 Key Finding

FHOD3 knockout in human embryonic stem cell-derived cardiomyocytes leads to sarcomere disorganization, impaired calcium handling, mitochondrial dysfunction, and reduced contractility.

Background: Inherited cardiomyopathy (ICM) is a genetic disorder characterized by abnormal myocardial structure and function, often progressing to heart failure. FHOD3, a member of the Formin gene family, plays a crucial role in cardiomyocyte cytoskeletal organization. Mutations in FHOD3 have been associated with various cardiomyopathies, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and left ventricular noncompaction (LVNC). However, the molecular mechanisms underlying FHOD3 deficiency-induced cardiomyopathy remain elusive. Methods: A FHOD3 knockout (FHOD3-/-) human embryonic stem cell (hESC) line was generated using the CRISPR/Cas9 system and subsequently differentiated into cardiomyocytes (hESC-CMs). Sarcomere structure, calcium handling, mitochondrial function, and contractility were evaluated via immunofluorescence, electron microscopy, Seahorse metabolic analysis, and high-definition video analysis, respectively. Transcriptomic sequencing was performed to identify differentially expressed genes and enriched pathways. Results: FHOD3-deficient hESC-CMs exhibited marked sarcomere disorganization and degradation, impaired calcium handling and compromised mitochondrial function, ultimately leading to reduced contractility. Transcriptomic analysis revealed significant downregulation of sarcomere-related genes and calcium-handling genes, with enrichment in pathways associated with cardiomyopathy and calcium signaling. Furthermore, FHOD3 deficiency triggered the phosphorylation of CaMKII (Thr286), a key regulator of cardiac hypertrophy and remodeling, contributing to the progression of heart failure. Treatment with the myosin activator Omecamtiv mecarbil (OM) partially restored contractility without affecting calcium handling, highlighting its potential as a therapeutic strategy. Conclusions: Our study establishes a valuable human-derived model for investigating the molecular mechanisms of FHOD3 deficiency-induced cardiomyopathy. This model allows for extensive investigation into the phenotypes caused by FHOD3 deficiency and identifies CaMKII activation as a crucial factor contributing to the HF phenotype. Additionally, this model serves as an important tool for discovering novel therapeutic agents, and we demonstrate that OM can partially improve myocardial function in FHOD3 KO hESC-CMs.

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Interleukin-10-engineered mesenchymal stem/stromal cells exhibit robust immunomodulatory effects in vitro and in vivo
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-05093-3

Interleukin-10-engineered mesenchymal stem/stromal cells exhibit robust immunomodulatory effects in vitro and in vivo

Authors: Diego de Carvalho Carneiro, Cássio Santana Meira, Rosane Borges Dias, Vinícius Pinto Costa Rocha, Patrícia Kauanna Fonseca Damasceno, Josiane Dantas Viana Barbosa, Milena Botelho Pereira Soares

💡 Key Finding

MSC-IL-10 maintained mesenchymal phenotype and multipotency while exhibiting robust IL-10 expression.

Background: A dysregulated inflammatory response to infection can lead to sepsis, a leading cause of mortality worldwide, and effective anti-inflammatory therapies remain limited. Mesenchymal stem/stromal cells (MSCs) are attractive candidates as immunomodulatory agents. This study evaluated whether genetic modification of MSCs to express interleukin-10 (IL-10), a key anti-inflammatory cytokine, enhances their immunomodulatory effects. Methods: Bone marrow-derived MSCs from C57Bl/6 mice were genetically engineered by lentiviral transduction to express mouse IL-10 (MSC-IL-10). The immunomodulatory activity in vitro was assessed by co-cultures with macrophages stimulated with LPS and IFN-γ, as well as in Con A–stimulated splenocytes. BALB/c mice subjected to lipopolysaccharide (LPS)-induced endotoxemia were treated with vehicle, dexamethasone, wild-type MSCs (MSC-WT), or MSC-IL-10. Survival, plasma cytokines, leukocyte profiles, CD11b⁺ inflammatory cells, and organ histopathology and biodistribution were evaluated in vivo. Results: MSC-IL-10 maintained the mesenchymal phenotype and multipotent characteristics while exhibiting robust IL-10 expression. In in vitro assays, MSC-IL-10 significantly decreased the production of the cytokines TNF-α, IL-1β, IL-6, IL-12 or Nos2 expression by stimulated macrophages or splenocytes, demonstrating superior immunomodulatory effects compared to MSC-WT. In in vivo mice models, MSC-IL-10 significantly reduced systemic pro-inflammatory cytokines, restored circulating leukocyte counts, and attenuated CD11b⁺ (Mac-1 integrin) inflammatory cell recruitment, surpassing MSC-WT-treated groups. Importantly, MSC-IL-10 mitigated tissue damage mainly to lungs and exhibited biodistribution to liver, lungs and spleen in LPS-challenged mice. Conclusions: These results support an enhanced immunomodulatory effect of IL-10-expressing MSCs as a promising cell-based therapeutic approach for sepsis and other inflammatory and immune mediated disorders.

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