Stem Cells Translational Medicine最新文献

{"title":"Cell therapy for stroke and spinal cord injury in clinical trials.","authors":"Yiping Fan, Si Tau Wong, Eyleen L K Goh, Jerry K Y Chan","doi":"10.1093/stcltm/szaf082","DOIUrl":"10.1093/stcltm/szaf082","url":null,"abstract":"<p><p>Brain injury describes a variety of injuries to the tissues and blood vessels in the head. It can be external such as in road accident or physical assaults or internal such as a stroke. Regardless, they are largely incurable with a long route to recovery with symptoms-relieving medications and rehabilitation. As such, many therapies were explored including cell therapy. However, not all were evidence based and in many instances banking of patients' desperation, many treatments were done without any evidence from clinical trials. Here, we reviewed clinical trials on clinicaltrials.gov for stroke and spinal cord injury where there are cellular therapies transplanting neural, mesenchymal, and haemopoietic cells. We present and discuss 40 trials involving cell therapies for stroke and 32 for spinal cord injuries that are either completed or active. Although some trials began as long as 20 years ago and have shown encouraging improvements in various scale scores for both stroke and spinal cord injury, cell transplantation for brain injuries remains an evolving field that requires further research before it can be established as a standard treatment.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12873748/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146126383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic effect of amniotic membrane mesenchymal stem cell-derived exosome-rich conditioned medium in cerebral palsy model.","authors":"Eun-Jung Yoon, Jiwon Jeong, Yunseo Choi, Dae Hwan Kim, Tae Myoung Kim, Ehn-Kyoung Choi, Yun-Bae Kim, Dongsun Park","doi":"10.1093/stcltm/szaf071","DOIUrl":"10.1093/stcltm/szaf071","url":null,"abstract":"<p><strong>Background: </strong>Cerebral palsy (CP), primarily caused by perinatal cerebral hypoxia and ischemia, is a devastating neurological disease in children characterized by motor, behavioral, and cognitive disorders. This study aimed to evaluate the therapeutic effects of amniotic membrane mesenchymal stem cell-derived exosome-rich conditioned medium (ERCM) in a CP model.</p><p><strong>Methods: </strong>ERCM components were analyzed using enzyme-linked immunosorbent assay. Biodistribution was examined via fluorescence-labeled ERCM in both normal and CP induced animals. In vitro, the neuroprotective effects of ERCM against lipopolysaccharide and potassium cyanide-induced cytotoxicity were assessed in human neural stem cells and oligodendrocyte progenitor cells, focusing on apoptosis, inflammation, and oligodendrocyte differentiation. In vivo, ERCM was injected into CP-induced animals, followed by evaluation of antiapoptotic and anti-inflammatory signaling, motor and cognitive function, and white matter integrity.</p><p><strong>Results: </strong>ERCM contained a broad array of growth factors and demonstrated enhanced retention in CP-affected brain regions. In vitro, ERCM significantly reduced apoptos is and inflammation, and promoted oligodendrocyte maturation via upregulation of Nkx2.2, CN Pase, and MBP. In vivo, ERCM treatment improved motor and cognitive performance, in hibited cell death and inflammatory responses, and increased expression of oligodendrocyte markers, including Nkx2.2, Olig2, CNPase, and MBP via increasing growth factor expression. Furthermore, ERCM attenuated demyelination in the corpus callosum, a region particularly vulnerable in CP.</p><p><strong>Conclusion: </strong>ERCM confers therapeutic benefits in CP by preserving neural stem and oligodendrocyte progenitor cells, modulating apoptosis and inflammation, and enhancing oligodendrocyte differentiation. Accordingly, ERCM may present a good candidate as a CP therapeutic agent.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12784200/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145935047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human induced pluripotent stem cell-derived neural stem/progenitor cell therapy for spinal cord injury: preclinical advances and translational perspectives.","authors":"Ryo Ogaki, Narihito Nagoshi, Hideyuki Okano, Masaya Nakamura","doi":"10.1093/stcltm/szaf073","DOIUrl":"10.1093/stcltm/szaf073","url":null,"abstract":"<p><p>Spinal cord injury (SCI) causes irreversible neurological damage and remains a major clinical challenge due to the lack of effective regenerative therapies. Human-induced pluripotent stem cells (hiPSCs) and their derivatives, hiPSC-derived neural stem/progenitor cells (hiPSC-NS/PCs), have demonstrated potential to promote neural repair and functional recovery. The world's first clinical trial using hiPSC-NS/PCs in the subacute phase of SCI has already been initiated. In contrast, chronic SCI-despite accounting for the majority of clinical cases-remains difficult to treat due to pathological barriers such as widespread demyelination, cavitation, scar formation, and persistent inflammation. Recent efforts to overcome these obstacles include combinatorial strategies incorporating rehabilitation, biomaterial scaffolds, pharmacological adjuvants, and robotic-assisted therapy as well as gliogenic or regionally patterned hiPSC-NS/PCs. Preclinical models have demonstrated that such multifaceted approaches can enhance graft survival, axonal regeneration, and functional recovery. In this review, we provide an overview of the biological characteristics, mechanisms of action, and recent advances in preclinical and clinical research on hiPSC-NS/PCs transplantation for SCI. We also discuss future perspectives and challenges toward clinical application. Collectively, these efforts underscore the diverse, innovative, and translational potential of hiPSC-based regenerative medicine for SCI.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12784199/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145934987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting metabolic dysfunction-associated steatotic liver disease risk using patient-derived induced pluripotent stem cells.","authors":"Yuanyuan Qin, Parth Chhetri, Elizabeth Theusch, Grace Lim, Sheila S Teker, Yu-Lin Kuang, Shahrbanoo Keshavarz Aziziraftar, Mohammad Hossein Mehraban, Antonio Munoz-Howell, Varun Saxena, Dounia Le Guillou, Aras N Mattis, Jacquelyn J Maher, Marisa W Medina","doi":"10.1093/stcltm/szaf066","DOIUrl":"10.1093/stcltm/szaf066","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is reversible at early stages, making early identification critical. We previously demonstrated that patient-derived induced pluripotent stem cells (iPSCs) carrying MASLD-associated genetic risk variants exhibit greater oleate-induced intracellular lipid accumulation than those without these variants. This study aimed to develop an iPSC-based MASLD risk predictor using functional lipid accumulation assessments. We quantified oleate-induced lipid accumulation in iPSCs from three cohorts: (1) CIRM (22 cases, 20 controls), (2) POST (18 cases, 16 controls), and (3) UCSF (4 cases, 8 controls). Data from the CIRM cohort was used to define an iPSC-based MASLD risk score, which was subsequently validated in the POST and UCSF cohorts. Lipid accumulation was consistently higher in MASLD iPSCs across cohorts. The risk score achieved 44% sensitivity/75% specificity in POST and 75%/100% in UCSF. These findings suggest that oleate-induced lipid accumulation in iPSCs may be a predictor of MASLD risk. Larger studies incorporating additional cellular phenotypes, clinical, and genetic data could enhance predictive accuracy for MASLD surveillance and prevention.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12784195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145935012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular vesicles from mesenchymal stromal cells primed with synthetic toll-like receptor 4 agonists treat hematopoietic acute radiation syndrome.","authors":"John A Kink, Matthew H Forsberg, Derek M Krismer, Anna S Thickens, Raghavan Chinnadurai, Alex S Chen, Daniel J Chacko, Melissa Graham, Peiman Hematti, Christian M Capitini","doi":"10.1093/stcltm/szaf068","DOIUrl":"10.1093/stcltm/szaf068","url":null,"abstract":"<p><p>Whole-body exposure to ionizing radiation can lead to cellular DNA damage to bone marrow (BM), causing lethal hematopoietic acute radiation syndrome (H-ARS). Extracellular vesicles (EVs) from human BM-derived mesenchymal stromal cells were primed with CRX-527 (CRX), a synthetic TLR4 agonist, characterized and tested as a radiomitigator therapy. Using a xenogeneic H-ARS mouse model, a single in vivo treatment with CRX-EVs administered 4 or 24 hours after lethal irradiation significantly improved weight loss, clinical scores and prolonged survival compared to control treatments. Ex vivo generation of CRX-EV educated monocytes (CRX-EEMos) were also effective in a H-ARS model when administered 24 hours after lethal irradiation. CRX-EVs or CRX-EEMos significantly promoted hematopoiesis in BM and potentially the spleen, leading to restoration of peripheral complete blood counts. CRX-EEMos showed increased gene expression of IL-6 and IL-10: enriched for PD-L1 but low for CD16 in CD14-expressing monocytes. Antisense inhibition of Let-7 microRNAs in CRX-EEMos suppressed IL-10 gene expression and protein secretion, implicating a novel role for Let-7 in radioprotection. CRX-EVs can effectively treat H-ARS by increasing the secretion of anti-inflammatory molecules while stimulating monocytes to promote hematopoiesis in BM. The potential for large-scale production of CRX-EVs as an \"off-the-shelf\" treatment for H-ARS makes them a potential medical countermeasure for radiological and nuclear threats.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12784198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145934974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The protection of mesenchymal stem cells in metabolic reprogramming and endothelial-mesenchymal transition in diabetic aortas.","authors":"Mingying Ling, Jingxian He, Xu Jia, Na Yu, Yiping Song, Xuehui Li, Congmin Tang, Wenzhuo Yu, Han Qiao, Chenglong Zhang, Zhen Zhang, Tianmin Ma, Chuanli Zhao, Yanqiu Xing","doi":"10.1093/stcltm/szaf077","DOIUrl":"10.1093/stcltm/szaf077","url":null,"abstract":"<p><p>Vascular remodeling, a precursor to atherosclerosis and coronary heart disease, is associated with high morbidity and mortality in individuals with diabetes. The roles of endothelial-mesenchymal transition (EndMT) and human umbilical cord mesenchymal stem cells (hUCMSCs) in this process remain unclear. In this study, we used db/db mice as a diabetic model to investigate the effect of hUCMSCs on metabolic reprogramming and vascular remodeling. We analyzed serum markers, tissue morphology, metabolomics, and endothelial cell-specific proteomics. The results demonstrated that vascular remodeling and EndMT were exacerbated in diabetes and alleviated by hUCMSCs. Metabolomic analysis identified 209 altered metabolites. Most metabolic intermediates were increased, while anti-inflammatory metabolites such as arachidonoyl ethanolamide and sphingosine were decreased in the diabetic state. Treatment with hUCMSCs restored these metabolites to near-normal levels, thereby improving metabolic reprogramming and the vascular microenvironment. Correspondingly, endothelial cell proteomics revealed increased levels of glycolytic enzymes, inflammatory factors, and EndMT markers, including mitogen-activated protein kinase kinase kinase 20 (Map3k20), disintegrin and metalloproteinase domain-containing protein 10 (Adam10), and integrin alpha-8 (Itga8), in diabetes; hUCMSC treatment downregulated these factors. Notably, KEGG and protein-protein interaction analyses indicated that hUCMSCs inhibited the Tgfb1i1/Rock1 axis within the TGF-beta pathway, which drives EndMT. We further verified the expression of these proteins through endothelial immunofluorescent co-staining and confirmed the role of Rock1 in high glucose-induced EndMT in vitro. This study elucidates a potential molecular mechanism and a therapeutic strategy for early atherosclerosis in diabetes and provides a foundation for evaluating endothelial states in vivo.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12803787/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145985647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular time machines unleashed: small-molecule-driven reprogramming to reverse the senescence.","authors":"Chunyin Tang, Zhen Zhang, Chunsong Yang, Luxin Li, Jie Li, Xuejiao Cheng, Wei Zhou, Yunzhu Lin, Linan Zeng, Lingli Zhang","doi":"10.1093/stcltm/szaf069","DOIUrl":"10.1093/stcltm/szaf069","url":null,"abstract":"<p><p>Cellular reprogramming, a method of \"resetting\" the epigenetic clock by reversing the differentiation state of cells, has emerged as a promising approach to anti-aging, offering new strategies to slow down the aging process. Researchers convert differentiated cells into a pluripotent stem cell state through transcription factors or chemicals, restoring cellular youthfulness and regenerative capacity. This technology holds potential for tissue repair, lifespan extension, organ function improvement, and treatment of age-related diseases. In addition, cell reprogramming provides a novel pathway for disease modeling and drug screening, potentially accelerating the development and clinical application of anti-aging drugs. However, it faces challenges including safety, efficiency, and ethical considerations. This article focuses on the prospects of small-molecule-induced cell reprogramming for anti-aging, covering its mechanisms, applications, current limitations, and future directions to facilitate clinical translation and breakthroughs in human healthspan extension.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12798543/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145967017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human umbilical cord mesenchymal stem cells alleviate colon epithelial apoptosis in ulcerative colitis by activating inositol-requiring enzyme 1/X-box binding protein 1 signaling.","authors":"Taoran Zhao, Wenyi Hou, Mengwei Wang, Zhenyu Feng, Xiaoni Feng, Heng Wang, Hong Zhao, Xiujuan Li, Shulin Hou, Guoping Zheng, Xiaozheng Zhang, Jun Xie","doi":"10.1093/stcltm/szaf075","DOIUrl":"10.1093/stcltm/szaf075","url":null,"abstract":"<p><strong>Background: </strong>Ulcerative colitis (UC), a chronic inflammatory gastrointestinal disease, is characterized by disrupted intestinal barrier integrity and unresolved endoplasmic reticulum (ER) stress, which drives epithelial apoptosis and disease progression. While mesenchymal stem cells (MSCs), particularly human umbilical cord-derived MSCs (hUC-MSCs), have shown therapeutic potential in UC, their mechanisms in modulating ER stress remain unclear. This study aimed to investigate the role of hUC-MSCs in alleviating ER stress-induced epithelial damage and elucidate the underlying molecular pathways in a murine colitis model and in vitro systems.</p><p><strong>Results: </strong>Intraperitoneal administration of hUC-MSCs significantly attenuated dextran sulfate sodium (DSS)-induced colitis in mice. Histological analysis revealed restored crypt architecture and reduced epithelial apoptosis. Transcriptomic profiling demonstrated that hUC-MSCs reduced differentially expressed genes in inflammatory bowel disease-related and ER stress response pathways in colon tissues. Mechanistically, hUC-MSCs activated the IRE1/XBP1 axis, increasing Xbp1 splicing and suppressing pro-apoptotic Bcl2l11 expression. In vitro, hUC-MSC-conditioned medium protected colon epithelial cells from TNF-α-induced apoptosis via IRE1/XBP1 activation, an effect abolished by the IRE1 inhibitor 4μ8C.</p><p><strong>Conclusions: </strong>Our findings demonstrate that hUC-MSCs alleviate UC by mitigating ER stress through IRE1-mediated Xbp1 splicing, thereby reducing epithelial apoptosis and promoting mucosal repair. This study provides a mechanistic foundation for MSC-based therapies targeting ER stress in inflammatory bowel diseases.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12808544/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical efficacy and safety of allogeneic adipose-derived stem cells ELIXCYTE in chronic kidney disease: a phase I/II study.","authors":"Yi-Chun Lin, Yi-Pei Hung, Ya-Chung Tian, Ming-Ju Wu, Han-Chun Lin, Szu-Ying Chen, Mai-Szu Wu, Hung-Yi Chiou","doi":"10.1093/stcltm/szaf076","DOIUrl":"10.1093/stcltm/szaf076","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) poses a significant global health burden by reducing quality of life and increasing mortality. Current therapies remain inadequate in halting its progression, necessitating novel treatments to improve outcomes. Adipose-derived stem cells (ADSCs) have emerged as a promising therapeutic option. Phase I/II clinical trials evaluated the efficacy, safety, and tolerability of ELIXCYTE in slowing CKD progression. This multicenter, randomized, open-label study monitored estimated glomerular filtration rate (eGFR) changes over a 48-week period following a single intravenous infusion of ADSCs. Participants were allocated to one of three dosage groups, with primary outcomes assessing eGFR changes and secondary outcomes focusing on safety and tolerability. Results confirmed a favorable safety profile, with no dose-limiting toxicities observed in the low- and moderate-dose groups. Group-based trajectory modeling (GBTM) indicated that, overall, 88.24% of patients exhibited a trend of improvement or stabilization. In the low-dose group, 72.23% of patients demonstrated a stable trend, which was more consistent than in other dosage groups. Furthermore, patients with CKD stage 3B showed a numerically higher proportion of improving trajectories compared to those with stage 4 disease. The low-dose ADSC group exhibited a trend toward more favorable renal function trajectories and fewer adverse events than higher doses, suggesting that lower dosing may provide a balanced profile of safety and potential efficacy. However, despite the preliminary results indicating that ELIXCYTE may effectively slow CKD progression, further large-scale clinical trials are necessary to corroborate these findings and verify the efficacy of ADSC treatment.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12815603/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146004142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mesenchymal stem cell-derived exosome delivery of let-7a-5p enhances macrophage efferocytosis via Arid3a/Mertk axis in acute-on-chronic liver failure.","authors":"Junyi Wang, Zhihui Li, Zhouhan Wang, Wei Liang, Shibo Meng, Junfeng Chen, Jialei Wang, Jing Zhang, Bingliang Lin","doi":"10.1093/stcltm/szaf058","DOIUrl":"10.1093/stcltm/szaf058","url":null,"abstract":"<p><strong>Background: </strong>Acute-on-chronic liver failure (ACLF) is a severe clinical syndrome with a high mortality rate and limited therapeutic options. Macrophage efferocytosis plays an essential role in maintaining tissue homeostasis, and its dysfunction may be associated with the pathogenesis of ACLF. We previously found that mesenchymal stem cell (MSC) treatment in ACLF mice promoted macrophage M2 polarization and elevated the efferocytosis-related protein Mertk, but the underlying mechanisms remained unclear.</p><p><strong>Methods: </strong>The role of efferocytosis was investigated in liver tissues from ACLF patients and an ACLF mouse model treated with MSC-derived exosomes (MSC-Exos). In vitro experiments utilizing lipopolysaccharide-induced M1 macrophages were conducted to dissect the underlying mechanism, targeting the miRNA let-7a-5p. Engineered exosomes (MSC-Exoslet-7a-5p) were developed via electroporation to validate the therapeutic potential.</p><p><strong>Results: </strong>Impaired macrophage efferocytosis in liver tissues correlated with poor prognosis in ACLF patients. Treatment with MSC-Exos significantly improved histological morphology, liver function and enhanced efferocytosis in ACLF mice. Mechanistically, MSC-Exos delivered let-7a-5p to M1 macrophages, which downregulated Arid3a and upregulated Mertk expression. Furthermore, engineered MSC-Exoslet-7a-5p promoted efferocytosis more effectively than unmodified exosomes.</p><p><strong>Conclusion: </strong>MSC-Exos enhance macrophage efferocytosis in ACLF via the let-7a-5p/Arid3a/Mertk axis. Engineered MSC-Exoslet-7a-5p, by boosting this pathway, provide a potential strategy for improving ACLF therapy.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"14 12","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12673206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145661954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}