IF 3.6 2区医学

STEM CELLS Pub Date : 2025-09-04 DOI: 10.1093/stmcls/sxaf059

Lars Thielecke, Kalpana Nattamai, Aishlin Hassan, Ingmar Glauche, Hartmut Geiger, Kerstin Cornils

{"title":"The impact of donor and recipient age on post-transplantation clonality in murine haematopoiesis.","authors":"Lars Thielecke, Kalpana Nattamai, Aishlin Hassan, Ingmar Glauche, Hartmut Geiger, Kerstin Cornils","doi":"10.1093/stmcls/sxaf059","DOIUrl":"https://doi.org/10.1093/stmcls/sxaf059","url":null,"abstract":"The sustained production of blood and immune cells is driven by a pool of hematopoietic stem cells (HSCs) and their offspring. Due to the intrinsic heterogeneity of HSCs, the composition of emergent clones changes over time, leading to a reduced clonality in aging mice and humans. Theoretical analyses suggest that clonal conversion rates and clonal complexity depend not only on HSC heterogeneity, but also on additional stress conditions. These insights are particularly relevant in the context of stem cell transplantations, which still remain the only curative option for many hematologic diseases, increasingly considered viable for elderly individuals. However, age-related clonal changes post-transplantation are not well understood. To address this, we conducted a barcode-based assessment of clonality to investigate post-transplantation changes in both homo- and hetero-chronic settings, combined with low- and high-intensity pre-conditioned recipients. A robust and polyclonal engraftment was observed across all groups, but with distinct differences in barcode diversity. In particular, transplanted aged HSCs showed no changes in clonality, regardless of recipient age or pre-conditioning. Young HSCs transplanted into severely pre-conditioned old hosts as well as under reduced pre-conditioning, allowed for full lymphoid reconstitution, but showed substantial differences in clonality. Also, myeloid lineage bias, a hallmark of aged HSCs, was confirmed at a clonal level across all experimental groups. Overall, we found that aged HSCs generally maintain clonal diversity similar to young HSCs, but notable differences emerge under hetero-chronic conditions and varying pre-conditioning regimens. These findings challenge current paradigms and underscore the complex interactions between aging and transplantation conditions.","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144991166","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}

引用次数: 0

Molecular signature and regulatory network of human umbilical cord mesenchymal stromal cells as a niche for hematopoietic stem cells and progenitors. 人脐带间充质间质细胞作为造血干细胞和祖细胞生态位的分子特征和调控网络。

IF 3.6 2区医学

STEM CELLS Pub Date : 2025-09-02 DOI: 10.1093/stmcls/sxaf057

Pornprapa Srimorkun, Kittisak Suanpan, Korakot Atjanasuppat, Piamsiri Sawaisorn, Werapath Somchit, Teerapong Siriboonpiputtana, Oytip Nathalang, Suradej Hongeng, Sawang Petvises, Usanarat Anurathapan

{"title":"Molecular signature and regulatory network of human umbilical cord mesenchymal stromal cells as a niche for hematopoietic stem cells and progenitors.","authors":"Pornprapa Srimorkun, Kittisak Suanpan, Korakot Atjanasuppat, Piamsiri Sawaisorn, Werapath Somchit, Teerapong Siriboonpiputtana, Oytip Nathalang, Suradej Hongeng, Sawang Petvises, Usanarat Anurathapan","doi":"10.1093/stmcls/sxaf057","DOIUrl":"https://doi.org/10.1093/stmcls/sxaf057","url":null,"abstract":"The fate of hematopoietic stem cells (HSCs) is determined by a complex regulatory network supporting self-renewal and quiescence within a niche. Umbilical cord mesenchymal stromal cells (UC-MSCs) are classified as an alternative niche for the expansion of hematopoietic stem and progenitor cells (HSPCs). The molecular mechanisms by which UC-MSCs regulate hematopoiesis are still not fully understood. In this study, the cocultures of UC-MSCs and umbilical cord blood CD34+ (UCB-CD34+) cells were established. Immunophenotype, cell proliferation, and hematopoietic function of UCB-CD34+ cells were evaluated on days 0 to 7. UC-MSCs promoted UCB-CD34+ cell proliferation but were less effective at preserving their stemness. Notably, UC-MSCs promoted the myeloid lineage commitment, significantly observed on day 3. Integrative transcriptomic analysis highlighted the molecular signature and regulatory networks of UC-MSCs. The long non-coding RNA (lncRNA)-RNA binding protein (RBP) interaction network and lncRNA cis- and trans-regulatory networks were evident. The significant 3-gene modules and a set of 10-hub genes were identified in the protein-protein interaction (PPI) network, including RPS16, CD74, RPL35, COX7C, RPL38, RPS28, RPS27, RPS10, TARDBP, and TOMM7. These findings exemplify the niche activity of UC-MSCs in regulating cell differentiation, genomic stability maintenance, and modulation of the hematopoietic supportive niche. The transcriptional landscape, together with the identified regulatory networks, gene modules, and key hub genes provide new insights into the molecular mechanisms of UC-MSCs and establish a basis for refining ex vivo culture systems for therapeutic HSC expansion.","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937388","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}

引用次数: 0

Resistance to Naive and Formative Pluripotency Conversion in RSeT Human Embryonic Stem Cells. RSeT人胚胎干细胞对初始和形成性多能转化的抗性。

IF 3.6 2区医学

STEM CELLS Pub Date : 2025-08-22 DOI: 10.1093/stmcls/sxaf056

Kevin G Chen, Kory R Johnson, Kyeyoon Park, Dragan Maric, Forest Yang, Wenfang Liu, Yang C Fann, Barbara S Mallon, Pamela G Robey

{"title":"Resistance to Naive and Formative Pluripotency Conversion in RSeT Human Embryonic Stem Cells.","authors":"Kevin G Chen, Kory R Johnson, Kyeyoon Park, Dragan Maric, Forest Yang, Wenfang Liu, Yang C Fann, Barbara S Mallon, Pamela G Robey","doi":"10.1093/stmcls/sxaf056","DOIUrl":"https://doi.org/10.1093/stmcls/sxaf056","url":null,"abstract":"One of the most important properties of human embryonic stem cells (hESCs) is their ability to exist in primed and naive pluripotent states. Our previous meta-analysis indicated the existence of heterogeneous pluripotent states derived from diverse naive protocols. In this study, we characterized a commercial, RSeT-based pluripotent state under various growth conditions. Notably, RSeT hESCs can circumvent the hypoxic growth conditions required by naive hESCs, although some RSeT cells (e.g., H1 cells) exhibit much lower single-cell plating efficiency and display altered or significantly retarded cell growth under both normoxia and hypoxia. Importantly, RSeT hPSCs lack many transcriptomic hallmarks of naive and formative pluripotency (the phase between naive and primed states). Integrative transcriptome analysis suggests that our primed and RSeT hESCs are similar to the early stage of post-implantation embryos, in line with previously reported primary hESCs and early hESC cultures. Moreover, RSeT hESCs do not express naive surface markers such as SUSD2 and CD75 at significant levels. At the biochemical level, RSeT hESCs show differential dependence on FGF2 and co-independency on both Janus kinase (JAK) and TGFβ signaling in a cell line-specific manner. Thus, RSeT hESCs represent a previously unrecognized pluripotent state downstream of naive pluripotency. Our data suggest that human naive pluripotent potentials may be restricted in RSeT medium, which sustains FGF2 activity. Hence, this study provides new insights into pluripotent state transitions in vitro.","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937402","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}

引用次数: 0

Giant Panda Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Promote Dermal Fibroblast Proliferation and Wound Healing. 大熊猫脐带间充质干细胞衍生外泌体促进真皮成纤维细胞增殖和伤口愈合。

IF 3.6 2区医学

STEM CELLS Pub Date : 2025-08-22 DOI: 10.1093/stmcls/sxaf051

Yuliang Liu, Hongyan Li, Yuan Li, Donghui Wang, Jiasong Chen, Zhixiang Yuan, Rongrui Zhang, Mingyue Zhang, Zhigang Cai, Rong Hou, Junhui An

{"title":"Giant Panda Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Promote Dermal Fibroblast Proliferation and Wound Healing.","authors":"Yuliang Liu, Hongyan Li, Yuan Li, Donghui Wang, Jiasong Chen, Zhixiang Yuan, Rongrui Zhang, Mingyue Zhang, Zhigang Cai, Rong Hou, Junhui An","doi":"10.1093/stmcls/sxaf051","DOIUrl":"https://doi.org/10.1093/stmcls/sxaf051","url":null,"abstract":"Umbilical cord mesenchymal stem cell-derived exosomes (UC-MSC-Exos) represent a potential therapeutic solution for captive giant pandas. The aim of this study was elucidating the proteomic and microRNA (miRNA) profiles and discerning their functional roles constitutes an essential step towards comprehending their therapeutic mechanisms and optimizing their application in giant pandas. UC-MSC-Exos, isolated from the culture supernatant of giant panda umbilical cord mesenchymal stem cells (UC-MSCs) using classic ultracentrifugation, were characterized using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blotting (WB). Mass spectrometry analysis and high-throughput small RNA sequencing were performed to determine the proteomic and miRNA profiles. Further elucidation of the mechanism underlying the impact of miR-21-5p on DFs proliferation was achieved through dual-luciferase gene reporter assays. UC-MSC-Exos enhanced the proliferation and migration of giant panda dermal fibroblasts (DFs). These effects are partially attributed to growth factors such as platelet-derived growth factor (PDGF), transforming growth factor-β1 (TGF-β1), basic-fibroblast growth factor (b-FGF), and miR-21-5p. We found that miR-21-5p contributes to fibroblast proliferation by targeting the programmed cell death 4 (PDCD4) and reversion inducing cysteine rich protein with kazal motifs (RECK) genes, attenuating the expression of α-smooth muscle actin (α-SMA) induced by TGF-β1, and impeding the differentiation of fibroblasts into myoblasts. This study serves as a foundational framework for elucidating the functional properties of giant panda UC-MSC exosomes and offers valuable technical insights for the development of novel strategies to enhance wound healing in giant pandas.","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937409","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}

引用次数: 0

A novel trained mesenchymal stromal cell-based therapy, HXB-319, effectively controls progressive glomerulonephritis in a murine lupus model. HXB-319是一种基于间充质细胞的新型疗法，可有效控制小鼠狼疮模型的进行性肾小球肾炎。

IF 3.6 2区医学

STEM CELLS Pub Date : 2025-08-22 DOI: 10.1093/stmcls/sxaf040

Hulya Bukulmez, Adrienne T Dennis, Jane Reese-Koc, Sarah Kleinsorge-Block, Scott Sieg, Kristin B Highland, Steven N Emancipator

{"title":"A novel trained mesenchymal stromal cell-based therapy, HXB-319, effectively controls progressive glomerulonephritis in a murine lupus model.","authors":"Hulya Bukulmez, Adrienne T Dennis, Jane Reese-Koc, Sarah Kleinsorge-Block, Scott Sieg, Kristin B Highland, Steven N Emancipator","doi":"10.1093/stmcls/sxaf040","DOIUrl":"10.1093/stmcls/sxaf040","url":null,"abstract":"Introduction: Systemic lupus erythematosus (SLE) is driven by abnormal type-I and -II interferon activation, affecting a variety of immunocompetent cells. Mesenchymal stromal cells (MSCs) can modulate inflammation but often lack consistent potency. We developed HXB-319, an MSC-based therapy targeting inflammatory pathways in SLE. Previously, HXB-319 was shown to reduce alveolar hemorrhage in an SLE model. Here, we report its effects in a model of SLE that progresses to end stage kidney disease.Materials and methods: SLE-like disease was induced via intraperitoneal (IP) pristane injection in female BALB/cJ mice, followed by treatment with naïve MSCs or HXB-319. Over 9 months, survival and proteinuria were monitored. Upon euthanasia, kidneys were analyzed for histopathology and gene expression, splenocytes for immune subsets by flow cytometry, and serum for autoantibodies, growth factors, and cytokines.Results: HXB-319 significantly altered plasmacytoid dendritic cells, CD4+PD-L1+ cells, and both CD4+ and CD8+ RORγt+ (Th17 cells) subsets. HXB-310 lowered IFN-γ (P < 0.001), IL-17A (P = 0.01), BAFF (P < 0.05), and anti-dsDNA (P < 0.05), compared to untreated mice. HXB-319, but not naïve MSCs, significantly improved survival, halted progression of kidney disease, and stabilized proteinuria (all P < 0.05).Conclusion: HXB-319 demonstrates potential for mitigating SLE-associated glomerulonephritis, improving survival, and reducing proteinuria and glomerulosclerosis.","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525760","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}

引用次数: 0

Stem cells within the HPA axis in tissue homeostasis and disease. HPA轴内的干细胞在组织稳态和疾病中的作用。

IF 3.6 2区医学

STEM CELLS Pub Date : 2025-08-22 DOI: 10.1093/stmcls/sxaf039

Mario Schubert, Kaomei Guan, Charlotte Steenblock

{"title":"Stem cells within the HPA axis in tissue homeostasis and disease.","authors":"Mario Schubert, Kaomei Guan, Charlotte Steenblock","doi":"10.1093/stmcls/sxaf039","DOIUrl":"10.1093/stmcls/sxaf039","url":null,"abstract":"The hypothalamus-pituitary-adrenal (HPA) axis is crucial for energy metabolism, cardiovascular function, and stress response. Importantly, neuronal signaling circuits in the hypothalamus, along with hormones released from the pituitary and adrenal gland, must adapt to physiological demands or pathological conditions. Stem and progenitor cells are pivotal in this regulation, either by giving rise to distinct cell types or by interacting with progenitor or hormone-producing cells. While lineage-tracing studies in rodent models have explored the role of stem cells in the HPA axis, our understanding of the mechanisms underlying this dynamic tissue plasticity remains limited, especially in humans. Moreover, single-cell RNA sequencing has revealed significant heterogeneity among stem cell populations in the HPA-axis, raising questions about the functional relevance of individual subclusters during development and adulthood. In this concise review, we summarize current knowledge on stem cells in the HPA axis, focusing on their origins, localization of different stem cell populations, and sex-specific activity in maintaining tissue integrity. We further address their role under pathophysiological conditions, including metabolic disease, cancer, and stress. Lastly, we discuss emerging strategies for replacing lost or damaged stem or progenitor cells during aging, highlighting recent achievements in the in vitro differentiation of hypothalamic, pituitary, and adrenal stem cells.","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537603","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}

引用次数: 0

Contribution of cytokeratin 19-expressing cells towards islet regeneration induced by multipotent stromal cell secreted proteins. 表达细胞角蛋白19的细胞对多能基质细胞分泌蛋白诱导胰岛再生的贡献。

IF 3.6 2区医学

STEM CELLS Pub Date : 2025-08-22 DOI: 10.1093/stmcls/sxaf036

Nazihah Rasiwala, Gillian I Bell, Anargyros Xenocostas, David A Hess

{"title":"Contribution of cytokeratin 19-expressing cells towards islet regeneration induced by multipotent stromal cell secreted proteins.","authors":"Nazihah Rasiwala, Gillian I Bell, Anargyros Xenocostas, David A Hess","doi":"10.1093/stmcls/sxaf036","DOIUrl":"10.1093/stmcls/sxaf036","url":null,"abstract":"Residual beta cell function has been documented in \"medalist\" patients who have lived with Type 1 diabetes (T1D) for >50 years. In addition, endocrine cell neogenesis first occurs in the developing human embryo from progenitor cells derived from pancreatic ductal epithelial structure. Thus, beta cell conversion from a dormant epithelial precursor remains a promising approach to regenerate islets during T1D. We have previously shown that intra-pancreatic (iPan) injection of Wnt pathway-stimulated conditioned media (Wnt+ CdM) generated from human bone marrow-derived multipotent stromal cells (MSC) contained islet regenerative factors that reduced hyperglycemia and recovered beta cell mass in streptozotocin-treated mice. However, the endogenous source of regenerated beta cells remains unknown. Herein, we employed cytokeratin 19 (CK19)-CreERT Rosa26-mTomato lineage-tracing mice to assess the endocrine conversion of CK19+ cells during MSC CdM-induced islet regeneration. Mice iPan-injected with Wnt+ CdM demonstrated reduced blood glucose levels and improved glucose tolerance compared to mice injected with unconditioned basal media. CdM-injected mice also showed increased islet number and beta cell mass, as well as CK19+ cells within regenerating islets. The frequency of insulin + cells that co-expressed tdTomato within dissociated pancreas samples observed via flow cytometry was 5-fold higher in Wnt+ CdM-injected mice (~5%) compared to basal media-injected controls (~1%). Collectively, in vivo lineage tracing revealed conversion of CK19+ cells to functional beta cells partially contributed to islet regeneration induced by Wnt-activated MSC CdM. Future studies are required to delineate alternate cell types and mechanisms participating in islet regeneration induced by direct delivery of MSC-CdM.","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12371234/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144256928","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}

引用次数: 0

A molecular systems architecture of the mesenchymal stromal cell microenvironment. 间充质间质细胞微环境的分子系统结构。

IF 3.6 2区医学

STEM CELLS Pub Date : 2025-08-22 DOI: 10.1093/stmcls/sxaf042

V A Shiva Ayyadurai, Prabhakar Deonikar, Vishvatha Radhakrishnan, Armand Keating

{"title":"A molecular systems architecture of the mesenchymal stromal cell microenvironment.","authors":"V A Shiva Ayyadurai, Prabhakar Deonikar, Vishvatha Radhakrishnan, Armand Keating","doi":"10.1093/stmcls/sxaf042","DOIUrl":"https://doi.org/10.1093/stmcls/sxaf042","url":null,"abstract":"A systems-level understanding of immunomodulatory, regenerative, and pro-/antifibrosis functions of mesenchymal stromal cells (MSCs) is critical to advance MSCs as a viable therapeutic option. Given the complexity of MSCs and their interactions with microenvironmental cells, a systems biology approach may enable such understanding to achieve practical objectives such as target identification, combination therapeutics, clinical strategies, and avoidance of adverse effects. In this study, a molecular systems architecture of MSCs microenvironment is developed to organize the complexity of biomolecular interactions between MSCs and other microenvironmental cells. This architecture provides a visual mapping of MSC interactions, identifies the complex crosstalk between MSCs and cells in the microenvironment, reveals potential targets, and offers a framework for creating future predictive, quantitative computational (in silico) models of the MSC microenvironment. The development of combination therapeutics, clinical strategies to improve therapeutic efficacy, and avoidance of adverse effects can be facilitated by such in silico models. However, it must all begin with a molecular systems architecture of MSCs-the objective and result of this study.","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":"43 9","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12371236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937412","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}

引用次数: 0

Healthy human induced pluripotent stem cell-derived cardiomyocytes exhibit sex dimorphism even without the addition of hormones. 健康的人类诱导多能干细胞衍生的心肌细胞即使在没有添加激素的情况下也表现出性别二态性。

IF 3.6 2区医学

STEM CELLS Pub Date : 2025-08-22 DOI: 10.1093/stmcls/sxaf038

Sophie E Givens, Abygail A Andebrhan, Eric G Schmuck, Aimee Renaud, An Xie, Somayeh Ebrahimi-Barough, Juan E Abrahante, Noah Stanis, Samuel Dudley, James R Dutton, Brenda M Ogle

{"title":"Healthy human induced pluripotent stem cell-derived cardiomyocytes exhibit sex dimorphism even without the addition of hormones.","authors":"Sophie E Givens, Abygail A Andebrhan, Eric G Schmuck, Aimee Renaud, An Xie, Somayeh Ebrahimi-Barough, Juan E Abrahante, Noah Stanis, Samuel Dudley, James R Dutton, Brenda M Ogle","doi":"10.1093/stmcls/sxaf038","DOIUrl":"10.1093/stmcls/sxaf038","url":null,"abstract":"Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a valuable cell type for studying human cardiac health and disease in vitro. However, it is not known whether hiPSC-CMs display sex dimorphism and therefore whether sex should be incorporated as a biological variable in in vitro studies that include this cell type. To date, the vast majority of studies that utilize hiPSC-CMs do not include both male and female sex nor stratify results based on sex because it is challenging to amass such a cohort of cells. Here, we generated 3 female and 3 male hiPSC lines from adult left ventricular cardiac fibroblasts as a resource for studying sex differences in in vitro cardiac models. We used this resource to generate hiPSC-CMs and maintained them in basal media without exogenous hormones. Functional assessment of CMs showed enhanced calcium handling in female-derived hiPSC-CMs relative to male. Bulk RNA sequencing revealed over 300 differentially expressed genes (DEGs) between male and female hiPSC-CMs. Gene ontology analysis of DEGs showed distinct differences in pathways related to cardiac pathology including cell-cell adhesion, metabolic processes, and response to ischemic stress. Differential expression of the sodium channel auxiliary unit SCN3B was found and validated through patch-clamp measurements of sodium currents, showing increased peak amplitude and window current in female hiPSC-CMs. These findings highlight the importance of considering sex as a variable when conducting studies to evaluate aspects of human cardiac health and disease related to CM function.","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12371235/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511285","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}

引用次数: 0

m6A mRNA demethylase FTO promotes chondrogenic differentiation of human bone marrow mesenchymal stem cells by targeting SMAD3. m6A mRNA去甲基化酶FTO通过靶向SMAD3促进人骨髓间充质干细胞成软骨分化。

IF 3.6 2区医学

STEM CELLS Pub Date : 2025-08-22 DOI: 10.1093/stmcls/sxaf035

Tao Shu, Dongfeng Zhang, Jiachun Li, Hanzhong Liu, Lukuan Cui, Juyuan Gu, Liang Wu, Wenfen Liu, Junming Wan, Xiaozuo Zheng

{"title":"m6A mRNA demethylase FTO promotes chondrogenic differentiation of human bone marrow mesenchymal stem cells by targeting SMAD3.","authors":"Tao Shu, Dongfeng Zhang, Jiachun Li, Hanzhong Liu, Lukuan Cui, Juyuan Gu, Liang Wu, Wenfen Liu, Junming Wan, Xiaozuo Zheng","doi":"10.1093/stmcls/sxaf035","DOIUrl":"10.1093/stmcls/sxaf035","url":null,"abstract":"Bone marrow mesenchymal stem cells (BMSCs) have chondrogenic differentiation potential to treat cartilage injury. N6 methyladenosine (m6A), one of the most prevalent mRNA modifications, has been reported to be crucial in cartilage disease. Herein, we further investigated the effects and underlying mechanisms in the modification of m6A on the chondrogenic differentiation of MSCs. This study showed that the m6A level was decreased in the chondrogenic differentiation of MSCs and m6A mRNA demethylation fat mass and obesity-associated protein (FTO) played an important role in these processes. The overexpression of FTO has been demonstrated to improve the levels of chondrogenic markers. We confirmed that FTO directly bound to SMAD3 mRNA and increased its demethylation, which promoted the chondrogenic differentiation of MSCs. We further indicated that the m6A \"reader\" YTHDF2 was probably related to the chondrogenic differentiation of MSCs. SiFTO attenuated the SiYTHDF2-increased mRNA stability of SMAD3, leading to the declining levels of chondrogenic markers. Collectively, these results reveal FTO could act as an important mediator of SMAD3 mRNA demethylation and improve the chondrogenic differentiation of MSCs.","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504332","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}

引用次数: 0

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