Ashok R Dinasarapu, Diane J Sutcliffe, Lauren Grychowski, Erkin Ozel, Anika Thite, Jasper E Visser, Ellen J Hess, Sharon M Kolk, H A Jinnah
{"title":"Modeling rare genetic disease with patient-derived induced pluripotent stem cells: reassessment of the minimum numbers of lines needed.","authors":"Ashok R Dinasarapu, Diane J Sutcliffe, Lauren Grychowski, Erkin Ozel, Anika Thite, Jasper E Visser, Ellen J Hess, Sharon M Kolk, H A Jinnah","doi":"10.1093/stcltm/szaf032","DOIUrl":"10.1093/stcltm/szaf032","url":null,"abstract":"<p><p>Induced pluripotent stem cells (iPSCs) are widely used to model human genetic diseases. The most common strategy involves collecting cells from relevant individuals and then reprogramming them into iPSCs. This strategy is very powerful, but finding enough individuals with a specific genetic disease can be challenging, especially since most are rare. In addition, making numerous iPSC lines is time-consuming and expensive. As a result, most studies have included relatively small numbers of iPSC lines, sometimes from the same individual. Considering the experimental variability obtained using different iPSC lines, there has been great interest in delineating the most efficient number of lines needed to achieve a robust and reproducible result. Several recommendations have been published, although most conclusions have been based on methods where experimental variance from individual cases is difficult to separate from technical issues related to the preparation of iPSCs. The current study used gene expression profiles determined by RNA sequencing (RNAseq) to empirically evaluate the impact of the number of unique individuals and the number of replicate iPSC lines from each individual for modeling Lesch-Nyhan disease (LND). This disease is caused by mutations in the HPRT1 gene, which encodes the enzyme hypoxanthine-guanine phosphoribosyltransferase. Results for detecting disease-relevant changes in gene expression depended on the analytical method employed, and whether or not statistical procedures were used to address multiple iPSC lines from the same individual. In keeping with prior studies, the best results were obtained with iPSC lines from 3-4 unique individuals per group. In contrast to prior studies, results were improved with 2 lines per individual, without statistical corrections for duplicate lines from the same individual. In the current study where all lines were produced in parallel using the same methods, most variance in gene expression came from technical factors unrelated to the individual from whom the iPSC lines were prepared.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"14 8","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12317316/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144769097","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}
Zepeng Zhang, Anhua Xu, Qian Zhou, Fei Wen, Fenghua Chen, Hansen Chen, Hu Wang, Liang Chen, Zhenyu Ju, Yuanlong Ge
{"title":"Repeated intravenous transplantation of human umbilical cord mesenchymal stem cells does not promote tumorigenesis in EGFR-mutated lung cancer mice.","authors":"Zepeng Zhang, Anhua Xu, Qian Zhou, Fei Wen, Fenghua Chen, Hansen Chen, Hu Wang, Liang Chen, Zhenyu Ju, Yuanlong Ge","doi":"10.1093/stcltm/szae065","DOIUrl":"10.1093/stcltm/szae065","url":null,"abstract":"<p><p>Mesenchymal stem cells (MSCs) are extensively studied in clinical trials for their potential therapeutic applications in degenerative and inflammatory diseases and disorders. Despite the lack of clinical evidence indicating that MSCs induce carcinogenesis, the immunosuppressive and proangiogenic functions of MSCs are considered as potential risks involving immune escape and tumor occurrence in programming tumor microenvironment. Previously, many groups had studied the tumorigenic safety of MSCs, but most of these studies were modeled in immuno-deficient mice with different types and sources of transplanted tumors, leaving varied and controversial conclusions. In this study, we developed a new xenograft model by repeatedly transplanting human umbilical cord mesenchymal stem cells (UC-MSCs) into transgenic mice via tail vein. These mice, carried a human-derived mutated EGFR with a normal immune system, were used to investigate whether UC-MSCs promote the occurrence of lung adenocarcinoma. The duration, dynamics, and pathological characteristics of the early stages of the disease were analyzed. In general, repeated transplantation of UC-MSCs neither accelerated the occurrence of lung cancer and the progression of bronchial alveolar carcinoma nor promoted a pro-tumor immune microenvironment. These results suggest that repeated transplantation of UC-MSCs does not increase the risk of lung cancer.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"14 8","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12403704/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144969717","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}
Yan Tang, Zhen-Yu Xu, Sai-Sai Song, Yan-Jue Song, Li-Jie Yang, Lei Wang, Yang Liu, Shu-Wen Qian, Zhi-Ying Pang, Qi-Qun Tang, Feng Yin
{"title":"Obesity hinders the efficacy of adipose-derived stem cells for knee osteoarthritis by reducing the proportion of DPP4+ stem cells.","authors":"Yan Tang, Zhen-Yu Xu, Sai-Sai Song, Yan-Jue Song, Li-Jie Yang, Lei Wang, Yang Liu, Shu-Wen Qian, Zhi-Ying Pang, Qi-Qun Tang, Feng Yin","doi":"10.1093/stcltm/szaf004","DOIUrl":"10.1093/stcltm/szaf004","url":null,"abstract":"<p><p>Osteoarthritis (OA) is the most prevalent and disabling joint disease, while adipose-derived stem cells (ASCs) have emerged as a promising therapeutic option in pre-clinical studies. However, the therapeutic efficacy of ASCs may be influenced by the source of these cells, especially in obese patients. This study compared the effects of intra-articular injections of ASCs from wild-type (WT) and ob/ob (OB) mice. Behavioral and histological analyses demonstrated that WT-ASCs significantly alleviated OA symptoms, restoring paw withdrawal thresholds and improving gait parameters while reducing cartilage degradation. In contrast, OB-ASCs only partially improved gait and did not significantly affect cartilage degeneration. Single-cell RNA sequencing of stromal vascular fractions from subcutaneous adipose tissue revealed distinct ASC subpopulations, with DPP4+ cells being notably reduced in obese mice. In vitro, OB-ASCs and high-fat-diet (HFD)-ASCs exhibited impaired proliferation and chondrogenesis but HFD-ASCs retained anti-inflammatory properties. Further investigation using fluorescence-activated cell sorting (FACS) isolated DPP4+ and DPP4- ASCs from WT mice, demonstrating that DPP4+cells had superior chondrogenic potential and reduced OA pain more effectively than DPP4- cells. These findings suggest that obesity impairs the therapeutic potential of ASCs in OA, primarily due to reduced proliferation and chondrogenesis, and highlight DPP4+ ASCs as a promising candidate for cell therapy in OA.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"14 8","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12413841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008435","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":"Evaluating the long-term efficacy of umbilical cord-derived mesenchymal stem cell therapy in retinitis pigmentosa: findings from a 1-to-4-year follow-up.","authors":"Ayse Oner, Neslihan Sinim Kahraman, Ali Unal","doi":"10.1093/stcltm/szaf034","DOIUrl":"10.1093/stcltm/szaf034","url":null,"abstract":"<p><strong>Background: </strong>The objective of this study was to assess the long-term effectiveness and safety of implanting mesenchymal stem cells derived from umbilical cord tissue (UC-MSC) in patients diagnosed with retinitis pigmentosa (RP).</p><p><strong>Methods: </strong>In this single-center study with a retrospective design, 669 eyes received suprachoroidal implantation of 5 million UC-MSCs. Postoperative assessments were conducted on the first day, third month, and every 6 months thereafter. At each visit, evaluations included best-corrected visual acuity (BCVA), anterior segment and fundus examinations, fundus photography, optical coherence tomography, and visual field (VF) tests. Multifocal electroretinography (mfERG) and full-field stimulus threshold (FST) testing were performed at baseline and every 6 months post-therapy. Procedure-related ocular and systemic complications were methodically documented.</p><p><strong>Results: </strong>A total of 669 eyes from 429 patients underwent surgical intervention. Bilateral procedures were performed in 240 patients, while 189 patients received surgery in only 1 eye. All 669 eyes completed the 12-month follow-up, while 265 eyes completed 2 years, 128 eyes completed 3 years, and 19 eyes completed 4 years of follow-up. No notable ocular or systemic complications were reported during the study duration. Statistically significant improvements in BCVA, VF, and mfERG central rings amplitude measurements were observed over time. FST testing revealed significant improvements in visual sensitivity in 27 patients.</p><p><strong>Conclusions: </strong>This investigation confirms the long-term benefits and safety profile of suprachoroidal UC-MSC therapy in cases of RP, demonstrating significant improvements in BCVA, VF, mfERG, and FST test outcomes. The data support the feasibility and potential of cell-based therapies as a promising and effective strategy for managing degenerative retinal diseases.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"14 8","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12409715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144993544","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}
Doil Park, Joo Ho Kim, Ji Eun Kim, Jaein Yoo, Eun Hee Kim, Oh Young Bang
{"title":"Effects of MSC-derived extracellular vesicles and dupilumab on the spleen and skin in a house dust mite-induced atopic dermatitis model.","authors":"Doil Park, Joo Ho Kim, Ji Eun Kim, Jaein Yoo, Eun Hee Kim, Oh Young Bang","doi":"10.1093/stcltm/szaf030","DOIUrl":"10.1093/stcltm/szaf030","url":null,"abstract":"<p><p>Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized as a biphasic T-lymphocyte-mediated disease involving T-helper cells. Dupilumab is a human monoclonal antibody that inhibits Th2-related cytokines and has recently been approved for patients with AD. However, the effects of dupilumab are relatively narrow in scope, primarily targeting cytokine-driven inflammatory pathways, with few reported systemic effects. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) could serve as an alternative therapeutic strategy for AD. This study aims to compare the effects of a single subcutaneous injection of EVs and biweekly subcutaneous injection of dupilumab on the skin and spleen in a house dust mite-induced model of AD. Clinical and histological analyses, including H&E and toluidine blue staining, showed that both EVs and dupilumab ameliorated AD in an animal model. Biodistribution analysis through live animal imaging revealed that subcutaneously injected EVs can migrate to the spleen, and flow cytometry analysis showed that EVs restored the splenic ratio of CD4+/CD8 + and spleen enlargement. Cytokine analysis of the skin and spleen showed that EVs effectively regulated both Th2 and Th1 responses, while dupilumab had limited effects on Th1 response. Further, mechanistic analyses revealed that both EVs and dupilumab ameliorated AD via the JAK/STAT signaling pathway. Thus, a single subcutaneous injection of EVs was equally effective as a biweekly subcutaneous injection of dupilumab in ameliorating AD. While dupilumab specifically targets and inhibits the Th2 immune response, clinical-scale EV therapeutics can regulate a broad spectrum of immune responses.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"14 8","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12288127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144699560","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}
Mallory L Lennon, Amy Frieman, Alyssa K Salazar, Igor Kogut, Ganna Bilousova, Jeffrey G Jacot
{"title":"Amniotic fluid collected from vaginal birth as a source of stem cells for clinical applications and disease modeling.","authors":"Mallory L Lennon, Amy Frieman, Alyssa K Salazar, Igor Kogut, Ganna Bilousova, Jeffrey G Jacot","doi":"10.1093/stcltm/szaf017","DOIUrl":"10.1093/stcltm/szaf017","url":null,"abstract":"<p><strong>Importance: </strong> Amniotic fluid is a promising source of autologous cells for disease modeling, drug screening, and regenerative medicine applications. However, current methods of collecting amniotic fluid are invasive, and samples are limited to pregnancies that require amniocentesis or cesarean section.</p><p><strong>Objective: </strong> The purpose of this study was to determine whether amniotic fluid cells could be isolated and cultured from amniotic fluid collected during vaginal deliveries.</p><p><strong>Intervention: </strong> Amniotic fluid samples were obtained during delivery of 4 neonates, 3 of which had been prenatally diagnosed with hypoplastic left heart syndrome (HLHS) in utero. Adherent amniotic fluid cells were assessed for maternal cell contamination, proliferation rate, surface marker expression, and differentiation potential. Amniotic fluid cells were also reprogrammed to induced pluripotent stem cells (iPSCs) and differentiated into functional cardiomyocytes.</p><p><strong>Results: </strong>Amniotic fluid cells collected from vaginal deliveries showed similar surface marker phenotype and differentiation characteristics to amniotic fluid-derived mesenchymal stem cells collected from amniocentesis and cesarean section. Amniotic fluid cells collected during vaginal births of both neonates with HLHS and one neonate with typical heart geometry could be reprogrammed to iPSCs and differentiated to a cardiac lineage with high efficiency. Conclusions and Relevence: These findings suggest that amniotic fluid collected from vaginal births is a readily available source of patient-specific stem cells for banking, in vitro disease modeling, and regenerative medicine applications.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"14 7","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12188528/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144485719","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}
Anthony Atala, John C Bischof, Christopher S Chen, John P Fisher, David L Hermanson, Charles L Howe, Walter C Low, Zhen Ma, David H McKenna, Sean P Palecek, Johnna S Temenoff, Brenda M Ogle
{"title":"The need for an organoid manufacturing, preservation, and distribution center.","authors":"Anthony Atala, John C Bischof, Christopher S Chen, John P Fisher, David L Hermanson, Charles L Howe, Walter C Low, Zhen Ma, David H McKenna, Sean P Palecek, Johnna S Temenoff, Brenda M Ogle","doi":"10.1093/stcltm/szaf031","DOIUrl":"10.1093/stcltm/szaf031","url":null,"abstract":"<p><p>Organoids, which are tiny, lab-grown 3D structures that mimic some organizational and functional properties of human organs, are slowly transforming the face of systems and developmental biology, biomedical research, pharmaceutical testing, environmental toxin testing, and healthcare. Significant investments are essential for the mass production, preservation, and distribution of organoids, with the aim to accelerate innovation and progress across multiple fields-much like the investments made in cell and biologics manufacturing over the past 2 decades.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"14 7","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144584928","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}
Cesar Ulises Monjaras-Avila, Ana Cecilia Luque-Badillo, Nicholas J Carr, Anthony A Papp, Alan I So, Claudia Chavez-Munoz
{"title":"Use of adipose-derived stem cells on decellularized bladder scaffolds for functional bladder mucosa regeneration.","authors":"Cesar Ulises Monjaras-Avila, Ana Cecilia Luque-Badillo, Nicholas J Carr, Anthony A Papp, Alan I So, Claudia Chavez-Munoz","doi":"10.1093/stcltm/szaf033","DOIUrl":"10.1093/stcltm/szaf033","url":null,"abstract":"<p><p>This study explores the potential for adipocyte-derived stem cells (ASCs) to be used in bladder reconstruction. Current methods, such as enterocystoplasty, have significant limitations, making new approaches necessary. Tissue engineering, specifically using acellular scaffolds such as the bladder acellular matrix, offers a promising basis for this development. For this study, ASCs were isolated from adipose tissue derived from liposuction and co-cultured with urothelial cells (UC; SV-HUC) to induce transdifferentiation. Results indicate successful isolation and characterization of ASCs, displaying positive markers for stem cells. The co-culture of ASCs with SV-HUC cells resulted in changes resembling epithelial cells, indicating a potential transdifferentiation process, and is corroborated by the mRNA and protein levels. For the functional assay, urothelial-like cells were seeded onto decellularized bladder tissues. These findings demonstrate the successful transdifferentiation of ASCs into functional UC, presenting a promising strategy for bladder reconstruction and a potential alternative to current approaches.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"14 7","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236066/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144584878","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}
Charles M Bowen, Frederick Ditmars, Naiyou Liu, Jose Marri Abril, David Ajasin, William K Russell, Heather L Stevenson, Eliseo A Eugenin, Jeffrey H Fair, W Samuel Fagg
{"title":"Amniotic fluid reduces liver fibrosis by attenuating hepatic stellate cell activation.","authors":"Charles M Bowen, Frederick Ditmars, Naiyou Liu, Jose Marri Abril, David Ajasin, William K Russell, Heather L Stevenson, Eliseo A Eugenin, Jeffrey H Fair, W Samuel Fagg","doi":"10.1093/stcltm/szaf026","DOIUrl":"10.1093/stcltm/szaf026","url":null,"abstract":"<p><p>Regardless of the source of injury or metabolic dysfunction, fibrosis is a frequent driver of liver pathology. Excessive liver fibrosis is caused by persistent activation of hepatic stellate cells (HSCs), which is defined by myofibroblast activation (MFA) and the epithelial-mesenchymal transition (EMT). Strategies to prevent or reverse this HSC phenotype will be critical for successful treatment of liver fibrosis. We have previously shown that full-term, cell-free human amniotic fluid (cfAF) inhibits MFA and EMT in fibroblasts in vitro. We hypothesize that cfAF treatment can attenuate HSC activation and limit liver fibrosis. We tested if cfAF could prevent liver fibrosis or HSC activation in murine models of liver damage, 3-dimensional hepatic spheroids, and HSC cultures. Administering cfAF prevented weight loss and the extent of fibrosis in mice with chronic liver damage without stimulating deleterious immune responses. Gene expression profiling and immunostaining indicated that cfAF administration in carbon tetrachloride-treated mice reduced EMT- and MFA-related biomarker abundance and modulated transcript levels associated with liver metabolism, immune regulatory pathways, and cell signaling. cfAF treatment lowered MFA biomarker levels in a dose-dependent manner in ex vivo hepatic spheroids. Treating HSCs with cfAF in vitro strongly repressed EMT. Multiomics analyses revealed that it also attenuates TGFβ-induced MFA and inflammation-associated processes. Thus, cfAF treatment prevents liver fibrosis by safeguarding against persistent HSC activation. These findings suggest that cfAF may be a safe and effective therapy for reducing liver fibrosis and preventing the development of cirrhosis and/or hepatocellular carcinoma.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"14 7","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12232411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144576253","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":"Mettl7a alleviated bone loss in osteoporosis mice by targeting the O-GlcNAcylation of Bsp via m6A methylation.","authors":"Yantong Wang, Yangyang Cao, Zhipeng Fan","doi":"10.1093/stcltm/szaf024","DOIUrl":"10.1093/stcltm/szaf024","url":null,"abstract":"<p><p>Postmenopausal osteoporosis, a prevalent metabolic bone disease, elevates susceptibility to fragility fractures while imposing substantial healthcare costs and public health challenges. The profound interplay between BMSCs and surrounding extracellular matrix (ECM) proteins, which are highly rich in O-GlcNAcylation, play pivotal roles in the process of osteoporosis. M6A methylation plays a crucial regulatory role in the development of osteoporosis, while the crosstalk between m6A methylation and ECM O-GlcNAcylation remains mechanistically undefined. Here we found Mettl7a overexpression improved the impaired osteogenic capability of OVX-mBMSCs in vitro. Conditional knockout of Mettl7a in the mesenchyme (Prx1-cre;Mettl7af/f) accelerated bone loss of OVX mice. Mechanistically, Mettl7a promoted mBMSCs osteogenic differentiation by targeting the O-GlcNAcylation of Bsp, an ECM protein. Mettl7a regulated the expression and O-GlcNAcylation of Bsp through m6A methylation of Oga. We further demonstrated that Mettl7a-AAV treatment alleviated bone loss phenotype in osteoporosis mice via the O-GlcNAcylation of Bsp. Collectively, our findings reveal novel mechanistic intersections between ECM protein O-GlcNAcylation and m6A methylation, advancing the understanding of osteoporotic regulation.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"14 7","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12188527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144485721","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}