STEM CELLS最新文献

{"title":"Bridging the Translational Gap in Sex-Specific Alzheimer's Disease Using Human iPSC-Based Neural Cell Models.","authors":"Sopak Supakul, Romruedee Phisalaphong, Makalin Changchai, Hideyuki Okano","doi":"10.1093/stmcls/sxag058","DOIUrl":"https://doi.org/10.1093/stmcls/sxag058","url":null,"abstract":"<p><p>Alzheimer's disease (AD) exhibits marked sex differences in disease prevalence, progression, and therapeutic responsiveness, with women disproportionately affected by both cognitive decline and neuropathological burden. Although sex hormones such as estrogen, progesterone, and testosterone have demonstrated neuroprotective effects in experimental systems, clinical outcomes of hormone-based interventions remain inconsistent. Emerging evidence further indicates that sex-specific molecular programs extend beyond endocrine signaling alone and include cell type-specific transcriptional architectures established across the lifespan. Recent single-cell transcriptomic studies have suggested that biological sex fundamentally shapes multicellular brain vulnerability. However, prevailing preclinical systems incompletely model human endocrine aging, sex chromosome biology, and patient-specific genetic heterogeneity, thereby limiting translational relevance. Human induced pluripotent stem cell (iPSC)-derived neural systems provide a new platform for mechanistically interrogating sex-specific pathways within human genetic backgrounds. By preserving donor-specific genetic backgrounds and sex chromosome complement, iPSC-derived neurons, astrocytes, microglia, and multicellular systems enable controlled investigation of hormone-responsive phenotypes, APOE-associated mechanisms, and cell type-specific transcriptional programs. However, their developmental immaturity and incomplete representation of systemic aging, vascular, immune, and endocrine physiology limit direct extrapolation to patients. Integration of these cellular systems with human omics datasets, neuropathological observations, and clinical studies may therefore help address specific components of the translational gap in AD.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149178354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Paracrine Bone-Derived Senescent Secretome is Associated with Spatially Patterned ECM Remodeling and Altered Biomechanics in Human Brain Organoids.","authors":"Chanul Kim, Luke Daniel Ofria, Hossein Shaygani, Anannya Kshirsagar, Sai Kulkarni, Alan Y Liu, James L Kirkland, Annie Kathuria, Maryam Tilton","doi":"10.1093/stmcls/sxag057","DOIUrl":"https://doi.org/10.1093/stmcls/sxag057","url":null,"abstract":"<p><p>Aging is increasingly recognized as a systemic process, yet the mechanisms by which signals from senescent peripheral cells accelerate brain aging remain poorly defined. Here, we used chronic exposure of human cerebral organoids to the secretome of senescent osteocytes to investigate how peripheral aging signals from bone reshape brain tissue architecture. We combined spatially resolved optical fiber-based interferometry nanoindentation with transcriptomic and immunofluorescence profiling, revealing distinct mechanical features across complementary measurements, including lower apparent modulus in intact organoids and spatially localized regions of elevated modulus in cryosectioned specimens. This spatially heterogeneous biomechanical remodeling was accompanied by upregulation of extracellular matrix, inflammatory, and senescence pathways, and suppression of neurodevelopmental and synaptic gene networks. Our results suggest that chronic paracrine exposure to senescent osteocyte-derived secretome is associated with localized extracellular matrix-related remodeling and mechanical vulnerability in human brain tissue, providing insight into how peripheral cellular senescence may contribute to regional brain fragility during aging. These pilot-scale findings were obtained using a single iPSC line and a single conditioned-medium batch, with one to six experimental replicates per condition across assays; the mechanical analyses were exploratory.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149163614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Msl3-mediated H4K16ac suppresses 2C-like reprogramming by sustaining LINE1 expression in mouse embryonic stem cells.","authors":"Yuqing Zhu, Shuo Cao, Qingying Wang, Jingjing Sun, Qian Song, Shoudong Ye","doi":"10.1093/stmcls/sxag056","DOIUrl":"https://doi.org/10.1093/stmcls/sxag056","url":null,"abstract":"<p><p>Two-cell-like cells (2CLCs), a rare totipotent-like population within mouse embryonic stem cells (mESCs) cultures, serve as a valuable model for studying early embryonic events like zygotic genome activation. However, the molecular mechanisms restraining their spontaneous emergence remain elusive. Here, we identify Msl3, an essential component of the MSL complex that is required for H4K16ac deposition, as a key suppressor of 2C-like reprogramming. Msl3 mediated H4K16ac promotes the expression of LINE1 retrotransposons, which act as upstream repressors of the 2C-lineage master regulator Dux. Consequently, Msl3 depletion reduces LINE1 expression, de-represses Dux, and robustly activates 2C-specific genes. Furthermore, LINE1 inhibition leads to heterochromatin dispersal and fragmented nucleoli. Our findings unveil a novel MSL3-H4K16ac-LINE1-Dux axis that actively safeguards mESCs pluripotency by suppressing a latent 2C-like program.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149056667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring Australian Public Attitudes Toward Organoid Research and Use: A Cross-Sectional Study.","authors":"Eden G Robertson, Kate Hetherington, Maeve McGillycuddy, Megan Munsie, Anai Gonzalez-Cordero","doi":"10.1093/stmcls/sxag054","DOIUrl":"https://doi.org/10.1093/stmcls/sxag054","url":null,"abstract":"<p><p>Organoid technologies offer promising new ways to study human biology and develop innovative therapies. While their scientific potential is clear, public awareness and acceptability remain largely unexplored - critical factors for ethical and equitable implementation. We conducted the first national survey of Australians (N = 502) to assess awareness, knowledge, attitudes, and acceptability of organoid technology. Awareness of stem cells was high, but organoids were largely unfamiliar. After a brief explanatory video, participants appeared to have more accurate conceptual framing (e.g., organoids as \"research tools\" and \"mini-organs\"), though objective knowledge remained limited. There was strong support for organoids, and more people expressed willingness to donate cells for stem cell or organoid research than have previously done so. Acceptability was correlated with attitudes toward animal research, knowledge, and some sociodemographic factors. Overall, public endorsement of organoid technology appears high but conditional, underscoring the need for transparent governance, clear consent, and inclusive communication.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149035873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of carcinogenesis resistance in Anatolian blind mole-rat mesenchymal stem cells and assessment of transcriptomic signatures.","authors":"Nese Unver, Ece Tavukcuoglu, Betul Budak, Onurcan Sezginer, Suleyman Can Ozturk, Saniye Elvan Ozturk, Ekim Z Taskiran, Teoman Kankilic, Kazim Yalcin Arga, Gunes Esendagli","doi":"10.1093/stmcls/sxag051","DOIUrl":"10.1093/stmcls/sxag051","url":null,"abstract":"<p><strong>Background: </strong>Mesenchymal stem cells (MSCs) exhibit dual roles in tumor progression and therapy resistance. However, the blind mole-rat (BMR, Nannospalax xanthodon) exhibits extraordinary natural resistance to spontaneous and induced carcinogenesis, making its MSCs a subject of significant therapeutic interest. This study investigates BMR MSCs' and fibroblasts' resistance to the carcinogen N-methyl-N-nitrosourea (MNU).</p><p><strong>Methods: </strong>We examined the cellular behavior and transcriptomic expression differences of bone marrow-derived MSCs and also fibroblasts isolated and characterized from blind mole-rats after exposure to the chemical carcinogen MNU. Similar analyses were also performed on mouse, rat, and human-derived MSCs, and expression disparities between species were evaluated.</p><p><strong>Results: </strong>While MNU treatment significantly induced apoptosis and reduced cell viability in human and mouse MSCs, BMR MSCs maintained stable proliferation kinetics, viability, and multilineage differentiation potential. Transcriptomic profiling revealed species-specific gene expression patterns, highlighting unique adaptive responses in the BMR. In BMR fibroblasts, MNU treatment suppressed PI3K/Akt signaling and modulated mitochondrial oxidative phosphorylation, whereas BMR MSCs demonstrated a flexible signaling architecture that preserved cellular programming and p53-mediated transcriptional regulation. Cross-species analysis integrated with TCGA datasets identified LAMTOR3 as a critical p53-dependent tumor-protective node.</p><p><strong>Conclusion: </strong>The ability of BMR MSCs to maintain the p53-LAMTOR3 axis following MNU treatment, alongside the suppression of pro-tumoral SMAD signaling, suggests a robust evolutionary strategy to inhibit malignant transformation. These findings provide novel insights into the genomic integrity of the BMR and identify potential biomarkers and therapeutic targets for enhancing cancer resistance.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13641824/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149035892","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 therapy for ischemic stroke: bridging clinical evidence and translational challenges.","authors":"Samson Selvaraj","doi":"10.1093/stmcls/sxag052","DOIUrl":"10.1093/stmcls/sxag052","url":null,"abstract":"<p><p>Ischemic stroke remains a major cause of long-term disability worldwide. Despite advances in acute reperfusion therapies, many survivors experience persistent neurological deficits due to irreversible neuronal loss and limited endogenous repair, highlighting the need for effective regenerative strategies. Mesenchymal stem cells (MSCs) have emerged as promising candidates for cell-based therapy because of their multimodal paracrine effects, including immunomodulation, promotion of angiogenesis and neurogenesis, attenuation of neuroinflammation, and enhancement of endogenous neuroplasticity. This Concise Review synthesizes the current clinical evidence supporting MSC therapy for ischemic stroke, critically examines the biological and translational determinants of therapeutic efficacy, and discusses emerging strategies, including engineered MSCs, extracellular vesicle (EV)-based therapies, and integration with neurorehabilitation. A structured literature search of PubMed/MEDLINE, Embase, Web of Science, and the Cochrane Library through June 2026 prioritized randomized controlled trials, systematic reviews, and meta-analyses. The largest contemporary meta-analysis, encompassing 30 clinical studies and 1217 participants, confirmed the favorable safety profile of MSC therapy while emphasizing the need for larger, standardized randomized trials to establish definitive clinical efficacy. Available evidence indicates that MSC therapy is generally safe, with serious treatment-related adverse events being uncommon, and may improve neurological impairment and functional recovery. However, heterogeneity in cell source, manufacturing protocols, administration route, treatment timing, dosing strategies, and patient selection continues to limit definitive conclusions regarding efficacy. Future progress will depend on standardized Good Manufacturing Practice-compliant manufacturing, validated potency assays, optimized patient selection, identification of the optimal therapeutic window, and integration of engineered MSCs, EV-based therapies, and combination approaches with neuromodulation.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149015114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human umbilical cord mesenchymal stem cells enhance folliculogenesis and fertility in premature ovarian failure mice via regulating steroid synthesis.","authors":"Xingyu Xu, Jiaxuan Zhang, Yi Li, Xiaoyu Wang, Tonghui Zhu, Zhaohua Zhang, Hongli Li, Xiaolei Liang","doi":"10.1093/stmcls/sxag037","DOIUrl":"10.1093/stmcls/sxag037","url":null,"abstract":"<p><strong>Background: </strong>Premature ovarian failure (POF) is a dysfunction that severely impacts women's physiological health and reproductive function. Human umbilical cord mesenchymal stem cell (hUCMSC) transplantation offers a promising therapeutic option for restoring ovarian function. However, its efficacy and underlying mechanisms are not yet fully understood.</p><p><strong>Methods: </strong>A POF mouse model was established using cyclophosphamide induction, and hUCMSCs were transplanted into the ovaries through in situ injection. Treatment efficacy was evaluated by assessing hormone levels, estrous cycle, follicle count, and reproductive outcomes. Furthermore, metabolomic sequencing was performed on the ovarian tissues of mice to explore the mechanism underlying the therapeutic effect of hUCMSCs.</p><p><strong>Results: </strong>Compared with the POF control group, the hUCMSC treatment group showed significant improvements: primordial and primary follicle counts increased by 8-fold and 5-fold, respectively, while atretic follicle ratios decreased by 50%. Pregnancy rates in treatment group increased from 30% to 60%, with average litter sizes rising from 1.6 pups/litter to 4.1 pups/litter. The expression of key genes (Cyp11a1, Cyp19a1, Star) in the steroidogenesis pathway was significantly upregulated in ovarian tissues, which restored the levels of steroid hormones such as progesterone and thereby stabilized serum sex hormone levels.</p><p><strong>Conclusions: </strong>In situ injection of hUCMSCs can restore ovarian function and fertility in POF mice by reducing granulosa cell apoptosis and upregulating steroidogenesis pathways.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148987327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editor's Note: Hyaluronan Is Crucial for Stem Cell Differentiation into Smooth Muscle Lineage.","authors":"","doi":"10.1093/stmcls/sxag055","DOIUrl":"10.1093/stmcls/sxag055","url":null,"abstract":"","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":"44 10","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13661007/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149178346","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":"Transverse tibial transport accelerated of diabetic wound healing via enhanced Wnt/β-catenin-driven BMSCs mobilization and angiogenesis.","authors":"Baoping Deng, Xiaoyong Ge, Junjie Li, Weiping Deng","doi":"10.1093/stmcls/sxag049","DOIUrl":"10.1093/stmcls/sxag049","url":null,"abstract":"<p><strong>Background: </strong>The management of severe diabetic foot ulcers (DFUs) remains a major clinical challenge. Tibial cortex transverse transport (TTT) has emerged as an effective surgical intervention, but its underlying mechanism, particularly concerning stem cell mobilization and signaling pathways, is largely unknown.</p><p><strong>Methods: </strong>A diabetic DFU model was established in New Zealand white rabbits using Streptozotocin (STZ), followed by TTT surgery. Wound healing was evaluated through photography, H&E, and Masson's trichrome staining. Angiogenesis was assessed by high-resolution X-ray angiography and immunofluorescence. Bone marrow-derived mesenchymal stem cell (BMSC) mobilization was analyzed via CFU-F assays and flow cytometry. Serum levels of SDF-1α, CXCR4, VEGF, and Ang2 were measured by enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction. The activity of the Wnt/β-catenin pathway was determined by Western blot.</p><p><strong>Results: </strong>Tibial cortex transverse transport significantly accelerated wound closure and enhanced tissue regeneration, with improved epidermal/dermal restoration and collagen deposition. Consistently, neovascularization in wounds was markedly promoted. Mechanistically, TTT activated the Wnt/β‑catenin signaling pathway in BMSCs, which was associated with enhanced BMSC quantity, mobilization, and migration capacity. Inhibition of this pathway attenuated the TTT‑induced pro‑healing effects.</p><p><strong>Conclusion: </strong>Tibial cortex transverse transport promotes healing of DFUs primarily by activating the Wnt/β-catenin pathway in BMSCs, thereby enhancing their mobilization, homing, and pro-angiogenic capacity. This study reveals a key molecular mechanism underlying TTT's efficacy and supports its therapeutic potential for refractory Diabetic foot ulcer (DFU).</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148872290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EPLIN stabilizes cell-cell adhesion complexes to facilitate TGF-β1-induced fibroblastic differentiation of human periodontal ligament stem cells.","authors":"A-Hyeong Choi, Seon-Yle Ko, Young-Joo Jang","doi":"10.1093/stmcls/sxag053","DOIUrl":"10.1093/stmcls/sxag053","url":null,"abstract":"<p><strong>Objectives: </strong>Periodontal ligament stem cells (hPDLSCs) are essential for periodontal regeneration, yet the molecular mechanisms governing their differentiation into functional fibroblasts remain poorly understood. This study aimed to identify novel regulatory molecules of PDL fibroblastic differentiation and elucidate the role of epithelial protein lost in neoplasm (EPLIN) in the fibroblastic differentiation.</p><p><strong>Methods: </strong>hPDLSCs were differentiated into PDL fibroblasts using TGF-β1. A novel antibody (anti-LG45) identified EPLIN as a target antigen. Functional roles of EPLIN were investigated through siRNA-mediated depletion and ectopic overexpression. Phalloidin staining for F-actin and co-immunoprecipitation were performed to analyze adherens junction integrity.</p><p><strong>Results: </strong>TGF-β1 treatment successfully induced fibroblastic differentiation, as evidenced by significant increases in fibroblastic marker expressions, which were abolished by the TGF-β receptor inhibitor SB-431542. A novel anti-LG45 antibody was found to specifically recognize EPLIN in differentiated PDL fibroblasts. EPLIN depletion significantly reduced the fibroblastic differentiation and disrupted the typical elongated morphology of PDL fibroblasts. Mechanistically, EPLIN depletion led to filament fragmentation and cytoskeletal collapse, decoupled N-cadherin from the cytoskeleton, and accelerated cell proliferation. Conversely, ectopic overexpression of EPLIN-α or β was sufficient to inhibit proliferation and induce fibroblastic markers even without TGF-β1 stimulation.</p><p><strong>Conclusion: </strong>EPLIN is a key regulatory factor that stabilizes the linkage between the actin cytoskeleton and adherens junctions, maintaining the fibroblastic phenotype and preventing unscheduled proliferation in hPDLSCs. This study indicates the importance of cytoskeletal structural integrity in PDL differentiation. Under this circumstance, EPLIN serves as a regulator that maintains the fibroblastic differentiation state of hPDLSCs and prevents unscheduled proliferation.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13653676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149035936","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}