Stem Cell Research & Therapy•2025•DOI: 10.1186/s13287-025-04398-z
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.
Stem Cell Research & Therapy•2025•DOI: 10.1186/s13287-025-04755-y
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.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025049
Connexins (Cxs), also known as gap junction proteins, are structurally related transmembrane proteins and have been implicated in carcinogenesis. Although some evidence suggests that these proteins are tumor suppressors due to their reduced expression in cancers, recent research indicates their complicated roles in tumor progression during different stages, including metastasis. Here, we show that Cx58, which is upregulated in non-small cell lung cancer (NSCLC), is modulated by myocyte-enhancer binding factor 2B (MEF2B). Either Cx58 or MEF2B knockdown attenuates the migration and invasion of NSCLC cells by inducing cytoskeleton rearrangement. Additionally, the prometastatic role of Cx58 in NSCLC is demonstrated in vivo. In conclusion, our findings suggest that Cx58 is transcriptionally activated by MEF2B and is involved in the metastasis of NSCLC by regulating cytoskeleton organization. Targeting the MEF2B/Cx58 axis may be exploited as a modality for improving NSCLC therapy.
Stem Cell Research & Therapy•2024•DOI: 10.1186/s13287-024-04031-5
The Editor-in-Chief has retracted this article. The authors of this article subsequently contacted the journal to request to replace components of Figs. 1B, 6E, 6H and 7A. Further investigation raised concerns regarding the provenance of the replacement figures and the rationale behind the need to replace these figures. The Editor-in-Chief therefore no longer has confidence in the reliability of the data reported in this article. Author Yong-lan Wang has stated that all authors disagree with this retraction.
Chinese Traditional and Herbal Drugs•2026•DOI: 10.7501/j.issn.0253-2670.2026.16.20261632
Brain disease treatment is constrained by the blood-brain barrier (BBB), resulting in insufficient drug accumulation in the brain, nonspecific distribution, and immune clearance. Although synthetic nanocarriers improve pharmacokinetics, their long-term stability and biosafety remain uncertain. Plant-derived nanovesicles (PDNVs) have emerged as therapeutic and delivery platforms owing to natural lipid bilayers, biocompatibility, low immunogenicity, and scalability. PDNVs carry lipids, proteins, nucleic acids, and bioactive small molecules, integrating delivery capability with intrinsic therapeutic activity. Component-structure theory interprets multicomponent systems through elemental structure, quantitative-ratio structure, and phase structure. From this perspective, PDNVs are natural composite nanovesicles formed by ordered integration of endogenous components within membrane-confined spaces. This review examines relationships among PDNVs composition, membrane architecture, BBB-crossing delivery, and therapeutic effects in brain diseases, and summarizes engineering strategies for functional optimization. It provides an analytical framework for rational design, quality control, and optimization of PDNVs as central nervous system drug delivery platforms. The review cites experimental evidence including grapefruit-derived nanovesicles for intestinal macrophage targeting, ginger-derived exosomes for glioblastoma, ginseng-derived exosome-like nanoparticles for active BBB penetration, and Momordica charantia small extracellular vesicles mitigating neuronal ferroptosis via GPX4 ubiquitination inhibition in ischemic stroke. These studies demonstrate PDNVs' dual role in preserving endothelial integrity while modulating the tumor microenvironment, and their capacity for nose-to-brain delivery in Parkinson's disease models. The component-structure framework enables systematic engineering of PDNVs for enhanced BBB penetration and therapeutic efficacy.