STEM CELLS最新文献_第3页

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

Human Obesity Decreases the Anti-inflammatory Functionality of Adipose Tissue-Derived Mesenchymal Stem/Stomal Cells by Upregulating IL-1β Expression. 人类肥胖通过上调IL-1β表达降低脂肪组织源性间充质干细胞/气孔细胞的抗炎功能。

IF 3.6 2区医学

STEM CELLS Pub Date : 2025-08-21 DOI: 10.1093/stmcls/sxaf058

Authors Li Xing, Xiangyang Zhu, Nattawat Klomjit, Lu Bo, Mina Al Saeedi, Amir Lerman, Alfonso Eirin, Lilach O Lerman

{"title":"Human Obesity Decreases the Anti-inflammatory Functionality of Adipose Tissue-Derived Mesenchymal Stem/Stomal Cells by Upregulating IL-1β Expression.","authors":"Authors Li Xing, Xiangyang Zhu, Nattawat Klomjit, Lu Bo, Mina Al Saeedi, Amir Lerman, Alfonso Eirin, Lilach O Lerman","doi":"10.1093/stmcls/sxaf058","DOIUrl":"https://doi.org/10.1093/stmcls/sxaf058","url":null,"abstract":"Background: Mesenchymal stromal cells (MSCs) possess therapeutic properties that mediate repair. Obesity impairs MSC functionality and therapeutic efficacy, possibly by eliciting dynamic modifications of epigenetic markers, like 5-hydroxymethylcytosine (5hmC). We hypothesized that human obesity alters the 5hmC landscape and anti-inflammatory capacity of adipose tissue-derived MSCs to activate the prominent inflammatory signaling mediator Interleukin (IL)-1β.Methods: Adipose tissue samples were collected from obese and lean individuals (body mass index ≥30 or < 30kg/m2, respectively, n = 11 each) during weight-loss or kidney donation surgery. MSCs were harvested and analyzed for 5hmC profiles (MeDIP-seq) and mRNA expression (RNA-seq) (n = 5 each). Subsequently, MSCs or a vehicle were injected into mice, (n = 6 each) and two-weeks later, kidneys were evaluated using in-vivo magnetic resonance imaging and ex-vivo studies. The role of interleukin(IL)-1β was then studied in-vitro in MSC-induced immunomodulation using siRNA in macrophages.Results: Compared to MSC from lean patients, obese-MSC genes showed 2,087 differential 5hmC modifications and 175 differential mRNA expression. Among them, 14 genes with overlapping alterations were involved in regulation of cytokine production, prominently IL-1β. Injecting obese MSCs elevated renal expression of IL-1β and M1 macrophage count but lowered kidney perfusion. Silencing IL-1β in obese-MSCs in vitro reduced M1 phenotype switching in co-incubated macrophages.Conclusion: Obesity induces epigenetic and gene expression changes in MSCs, particularly in IL-1β, associated with impaired anti-inflammatory functionality of MSCs. Targeting IL-1β could be a useful therapeutic approach to modulate the decline in MSC functionality resulting from obesity.","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937459","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

Brain pericytes derived from human pluripotent stem cells retain vascular and phagocytic functions under hypoxia. 由人多能干细胞衍生的脑周细胞在缺氧条件下仍能保持血管功能和吞噬功能。

IF 3.6 2区医学

STEM CELLS Pub Date : 2025-07-30 DOI: 10.1093/stmcls/sxaf055

Mingzi Zhang, Youbin Kim, Allison Bosworth, Julia T C W, Lina R Nih, Kassandra Kisler, Abhay P Sagare, Ruslan Rust

{"title":"Brain pericytes derived from human pluripotent stem cells retain vascular and phagocytic functions under hypoxia.","authors":"Mingzi Zhang, Youbin Kim, Allison Bosworth, Julia T C W, Lina R Nih, Kassandra Kisler, Abhay P Sagare, Ruslan Rust","doi":"10.1093/stmcls/sxaf055","DOIUrl":"https://doi.org/10.1093/stmcls/sxaf055","url":null,"abstract":"The integrity and function of the blood-brain barrier (BBB) are largely regulated by pericytes. Pericyte deficiency leads to BBB breakdown and neurological dysfunction in major neurological disorders including stroke and Alzheimer's disease (AD). Transplantation of pericytes derived from induced pluripotent stem cells (iPSC-PC) has been shown to restore the BBB and improve functional recovery in mouse models of stroke and pericyte deficiency. However, the molecular profile and functional properties of iPSC-PC under hypoxic conditions, similar to those found in ischemic and neurodegenerative diseases remain largely unexplored. Here, we demonstrate that iPSC-PC under severe hypoxia retain essential functional properties, including key molecular markers, proliferation rates, and the ability to migrate to host brain vessels via function-associated PDGFRB-PDGF-BB signaling. Additionally, we show that iPSC-PC exhibit similar clearance of amyloid beta (Aβ) neurotoxins from AD mouse brain sections under both normoxic and hypoxic conditions. These findings suggest that iPSC-PC functions are largely resilient to hypoxia, highlighting their potential as a promising cell source for treating ischemic and neurodegenerative disorders.","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144751874","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

Loss of peroxisome function promotes oxidative stress induced hematopoiesis. 过氧化物酶体功能的丧失促进氧化应激诱导的造血。

IF 3.6 2区医学

STEM CELLS Pub Date : 2025-07-29 DOI: 10.1093/stmcls/sxaf054

Emma A Schindhelm, Amada Blake, Megan M Constans, Kai Braaten, Aly L Thorn, Willa Durose, Maggie Lorentson, Ashish O Gupta, Paul J Orchard, Nancy Braverman, Gerald V Raymond, Troy C Lund

{"title":"Loss of peroxisome function promotes oxidative stress induced hematopoiesis.","authors":"Emma A Schindhelm, Amada Blake, Megan M Constans, Kai Braaten, Aly L Thorn, Willa Durose, Maggie Lorentson, Ashish O Gupta, Paul J Orchard, Nancy Braverman, Gerald V Raymond, Troy C Lund","doi":"10.1093/stmcls/sxaf054","DOIUrl":"https://doi.org/10.1093/stmcls/sxaf054","url":null,"abstract":"The role of peroxisomes in hematopoiesis remains poorly understood. The PEX1-Gly844Asp knock-in mouse lacks peroxisome formation and is peroxisome deficient. We observed that peroxisome deficient animals had up to 50% greater numbers of peripheral lymphocytes, neutrophils, and platelets which contained 2-fold greater reactive oxygen species (ROS, p = 0.0002). The marrow contained 2-fold greater numbers of cells and CFU (p = 0.0009 and < 0.0001, respectively). We found expansion (up to 3-fold) in the hematopoietic stem and progenitor cell (HSPC) compartment compared to that of WT animals demonstrated by: in vivo enumeration of LSK (p < 0.0001). Importantly through competitive bone marrow transplant experiments (primary and secondary) we show that peroxisome deficient cells outcompete wild type. We further demonstrate that peroxisome deficient HSPC harbor very high levels of intrinsic reactive oxygen species (ROS) which are attenuated after repopulation. Isolation of mesenchymal stem cells (MSC) isolated from peroxisome deficient mice also showed elevated levels of ROS. Finally, we found elevated levels of stem cell factor (SCF) in the plasma of peroxisome deficient mice and peroxisome deficient MSC expressed 2-fold more SCF compared to WT. Chemical induction of ROS also increased SCF expression by MSC. LSK expanded >10-fold greater in the absence on SCF on peroxisome deficient MSC than on WT MSC. In conclusion, the increase in HSPC numbers is, in part, driven by response to ROS in the microenvironment leading to increased SCF. These data add new insight into the role of peroxisomes in the bone marrow niche.","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144740766","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

Linking mitochondria, fatty acids and HSC expansion during infection: implications for aging and metabolic diseases. 在感染期间连接线粒体、脂肪酸和HSC扩张：对衰老和代谢疾病的影响。

IF 3.6 2区医学

STEM CELLS Pub Date : 2025-07-29 DOI: 10.1093/stmcls/sxaf053

Katherine Hampton, Alyssa Polski-Delve, Charlotte Hellmich, Stuart A Rushworth

{"title":"Linking mitochondria, fatty acids and HSC expansion during infection: implications for aging and metabolic diseases.","authors":"Katherine Hampton, Alyssa Polski-Delve, Charlotte Hellmich, Stuart A Rushworth","doi":"10.1093/stmcls/sxaf053","DOIUrl":"https://doi.org/10.1093/stmcls/sxaf053","url":null,"abstract":"In steady state, hematopoietic stem cells (HSCs) reside quiescently in their hypoxic niche with minimal mitochondrial activity, maintaining characteristically low levels of reactive oxygen species (ROS) and instead favoring glycolysis to meet their low energy requirements. However, stress, such as acute infection, triggers a state of emergency hematopoiesis during which HSCs expand more rapidly to produce up to ten-fold more downstream differentiated immune cells. To cope with this demand, HSCs increase their energy production by switching from low ATP-yielding glycolysis to high ATP-yielding mitochondrial oxidative phosphorylation. It is this metabolic switch that enables rapid HSC expansion and differentiation into downstream progeny to increase the immune cell pool and effectively clear the infection. This metabolic switch relies on the sufficient availability of healthy mitochondria as well as fuel in the form of free fatty acids to drive the necessary production of cellular components. This concise review aims to focus on how HSCs increase their mitochondrial content and fuel ATP production via fatty acid oxidation and the impact of HSC dysfunction during aging and other metabolic diseases.","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144740765","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

Exosomes derived from bone marrow-derived mesenchymal stem cells of exercise-trained mice improve wound healing by inhibiting macrophage M1 polarization. 运动训练小鼠骨髓间充质干细胞衍生的外泌体通过抑制巨噬细胞M1极化改善伤口愈合。

IF 4 2区医学

STEM CELLS Pub Date : 2025-07-21 DOI: 10.1093/stmcls/sxae081

Jiling Qiu, Yifan Zhao, Yingyi Chen, Yanxue Wang, Juan Du, Junji Xu, Lijia Guo, Yi Liu

{"title":"Exosomes derived from bone marrow-derived mesenchymal stem cells of exercise-trained mice improve wound healing by inhibiting macrophage M1 polarization.","authors":"Jiling Qiu, Yifan Zhao, Yingyi Chen, Yanxue Wang, Juan Du, Junji Xu, Lijia Guo, Yi Liu","doi":"10.1093/stmcls/sxae081","DOIUrl":"10.1093/stmcls/sxae081","url":null,"abstract":"Background: Engaging in appropriate exercise is advantageous for our well-being. We investigated whether exercise could affect the paracrine function of BMSCs and whether exosomes derived from treadmill exercise-trained mouse (Exo-tread) BMSCs could engender more pronounced effects on wound healing.Methods: First, the effects of treadmill exercise on mouse BMSCs biological functions, exosomes secretion quantity, and identification were assessed. Furthermore, we assessed the effects of Exo-tread on M1 macrophage by qPCR and FCM in vitro. Additionally, the expressions and phosphorylation status of p65 and p38 proteins were analyzed via Western blotting. For the in vivo component, we induced wound models of mice. Subsequently, we assessed the effects of Exo-tread using various methodologies including imaging, H&E, Masson, immunohistochemical, and immunofluorescence staining. To demonstrate whether Exo-tread could act through macrophages, we further depleted mouse macrophages.Results: Exercise accelerated the proliferation of BMSCs and the secretion of exosomes. In vitro, Exo-tread markedly decreased the expression of inflammatory factors while concurrently suppressing M1 polarization in mouse peritoneal macrophages compared with the Exo-ctrl group. These observed effects were potentially mediated by the reduction in the M1 polarization ratio, achieved through the inhibition of p65 and p38 phosphorylation. Similarly, in vivo experiments demonstrated that Exo-tread significantly enhanced wound healing by attenuating inflammatory cytokines and M1 macrophages.Conclusions: Exo-tread facilitates wound healing by mitigating the inflammatory response, achieved through a reduction in the M1 polarization ratio.","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264978","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

DNA hydroxy methylases Tet1 and Tet2 regulate bone aging and bone marrow stromal cell metabolism through the IGF-1/mTOR signaling axis. DNA羟甲基化酶Tet1和Tet2通过IGF-1/ mTOR信号轴调节骨老化和BMSC代谢。

IF 4 2区医学

STEM CELLS Pub Date : 2025-07-21 DOI: 10.1093/stmcls/sxaf026

Nicholas Smith, Dimitrios Cakouros, Feargal J Ryan, David J Lynn, Sharon Paton, Agnieszka Arthur, Stan Gronthos

{"title":"DNA hydroxy methylases Tet1 and Tet2 regulate bone aging and bone marrow stromal cell metabolism through the IGF-1/mTOR signaling axis.","authors":"Nicholas Smith, Dimitrios Cakouros, Feargal J Ryan, David J Lynn, Sharon Paton, Agnieszka Arthur, Stan Gronthos","doi":"10.1093/stmcls/sxaf026","DOIUrl":"10.1093/stmcls/sxaf026","url":null,"abstract":"The Ten-Eleven Translocases (Tet) family of DNA hydroxymethylases have recently been implicated in bone development, with Tet1 and Tet2 mediating Bone Marrow Stromal Cell (BMSC) growth and osteogenic differentiation. The present study investigated the effects of Tet1 and Tet2 deregulation on bone development and age-related bone loss, with respect to BMSC function. Histomorphometric and micro-CT analysis of skeletal parameters found significant reductions to trabecular structure and volume as well as reduced osteoblast numbers within the bone of Prx1:Cre driven Tet1 and Tet2 double knockout (TetDKO) mice at skeletal maturity. Moreover, these effects were exacerbated with age, particularly in male mice. In vitro, studies found a significant reduction in TetDKO BMSC osteogenic potential and a shift towards adipogenesis, as well as changes to DNA repair, proliferation, and senescence properties. RNA sequencing of BMSC derived from TetDKO male mice uncovered several differentially expressed genes, and an array of significantly enriched gene set pathways. Notably, Pappa2, involved in the regulation of IGF-1 signaling, was significantly differentially regulated, leading to a reduction in IGF-1 bioavailability and signaling in BMSC and differentiated osteoblasts. Furthermore, changes in mTOR activity in TetDKO animals indicated altered metabolic activity, differentiation, and proliferation capabilities of TetDKO BMSC. These findings indicate that Tet1 and 2 regulate the IGF-1 regulatory element, Pappa2, where deregulation of Tet1 and Tet2 in BMSC can disrupt this pathway leading to enhanced bone loss and premature aging. Targeting these novel regulatory pathways may offer new therapeutic approaches for the treatment of age-related bone loss.","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12277962/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961839","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