{"title":"KLF5调控骨髓干细胞外泌体来源的miR-152-3p改善心肌梗死后室性心律失常","authors":"Chen Wu, Xin-Yue Zou, Yi-Wen Jiang, Da-Wei Lin, Feng Jiang, Yao-Sheng Wang","doi":"10.1155/sci/5572221","DOIUrl":null,"url":null,"abstract":"<p><p>Cardiac fibroblasts (CFs) are activated into cardiac myofibroblasts (CMFs) in myocardial infarction (MI) and promote fibrosis, playing a crucial role in deteriorating cardiac function and inducing fatal arrhythmias. Transplantation of bone marrow mesenchymal stem cells (BMSCs) has emerged as a promising therapeutic approach for ischemic heart diseases, including MI. Recent studies have indicated that BMSCs can modulate the survival, differentiation, and antifibrotic activity of CFs. Kruppel-like factor 5 (KLF5) is a significant transcription factor involved in maintaining stem cell properties. In this study, we aimed to investigate whether overexpression of KLF5 could enhance the cardioprotective characteristics of BMSCs, particularly in terms of mitigating structural and electrical remodeling. Our in vivo experiments revealed that transplantation of KLF5-overexpressing BMSCs in mice with MI led to a substantial reduction in ventricular fibrosis and the occurrence of ventricular arrhythmias (VAs). In vitro coculture experiments demonstrated that BMSCs could inhibit CFs activation and cytoskeleton protein bundling induced by hypoxia through paracrine effects, resulting in reduced expression of α-SMA and Collagen I. Furthermore, coculturing BMSCs significantly reduced the expression of connexin 43, alleviated hypoxia, increased the expression of inward-rectifier K<sup>+</sup> current (Kir), and decreased voltage-dependent K<sup>+</sup> (Kv) currents. Mechanistically, KLF5 enhanced the effects of BMSCs by facilitating the transfer of miR-152-3 p from BMSCs-derived exosomes to CFs. Overall, our findings show that BMSCs transplantation promotes the recovery of cardiac function and reduces the incidence of arrhythmias by inhibiting CFs activation and modulating CFs Kir current remodeling. Additionally, overexpression of KLF5 enhances the cardioprotective effects of BMSCs.</p>","PeriodicalId":21962,"journal":{"name":"Stem Cells International","volume":"2025 ","pages":"5572221"},"PeriodicalIF":3.3000,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12357777/pdf/","citationCount":"0","resultStr":"{\"title\":\"KLF5 Regulation of Exosome-Derived miR-152-3p From Bone Marrow Stem Cells Improves Ventricular Arrhythmia After Myocardial Infarction.\",\"authors\":\"Chen Wu, Xin-Yue Zou, Yi-Wen Jiang, Da-Wei Lin, Feng Jiang, Yao-Sheng Wang\",\"doi\":\"10.1155/sci/5572221\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Cardiac fibroblasts (CFs) are activated into cardiac myofibroblasts (CMFs) in myocardial infarction (MI) and promote fibrosis, playing a crucial role in deteriorating cardiac function and inducing fatal arrhythmias. Transplantation of bone marrow mesenchymal stem cells (BMSCs) has emerged as a promising therapeutic approach for ischemic heart diseases, including MI. Recent studies have indicated that BMSCs can modulate the survival, differentiation, and antifibrotic activity of CFs. Kruppel-like factor 5 (KLF5) is a significant transcription factor involved in maintaining stem cell properties. In this study, we aimed to investigate whether overexpression of KLF5 could enhance the cardioprotective characteristics of BMSCs, particularly in terms of mitigating structural and electrical remodeling. Our in vivo experiments revealed that transplantation of KLF5-overexpressing BMSCs in mice with MI led to a substantial reduction in ventricular fibrosis and the occurrence of ventricular arrhythmias (VAs). In vitro coculture experiments demonstrated that BMSCs could inhibit CFs activation and cytoskeleton protein bundling induced by hypoxia through paracrine effects, resulting in reduced expression of α-SMA and Collagen I. Furthermore, coculturing BMSCs significantly reduced the expression of connexin 43, alleviated hypoxia, increased the expression of inward-rectifier K<sup>+</sup> current (Kir), and decreased voltage-dependent K<sup>+</sup> (Kv) currents. Mechanistically, KLF5 enhanced the effects of BMSCs by facilitating the transfer of miR-152-3 p from BMSCs-derived exosomes to CFs. Overall, our findings show that BMSCs transplantation promotes the recovery of cardiac function and reduces the incidence of arrhythmias by inhibiting CFs activation and modulating CFs Kir current remodeling. Additionally, overexpression of KLF5 enhances the cardioprotective effects of BMSCs.</p>\",\"PeriodicalId\":21962,\"journal\":{\"name\":\"Stem Cells International\",\"volume\":\"2025 \",\"pages\":\"5572221\"},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2025-08-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12357777/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Stem Cells International\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1155/sci/5572221\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q2\",\"JCRName\":\"CELL & TISSUE ENGINEERING\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Stem Cells International","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1155/sci/5572221","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"CELL & TISSUE ENGINEERING","Score":null,"Total":0}
KLF5 Regulation of Exosome-Derived miR-152-3p From Bone Marrow Stem Cells Improves Ventricular Arrhythmia After Myocardial Infarction.
Cardiac fibroblasts (CFs) are activated into cardiac myofibroblasts (CMFs) in myocardial infarction (MI) and promote fibrosis, playing a crucial role in deteriorating cardiac function and inducing fatal arrhythmias. Transplantation of bone marrow mesenchymal stem cells (BMSCs) has emerged as a promising therapeutic approach for ischemic heart diseases, including MI. Recent studies have indicated that BMSCs can modulate the survival, differentiation, and antifibrotic activity of CFs. Kruppel-like factor 5 (KLF5) is a significant transcription factor involved in maintaining stem cell properties. In this study, we aimed to investigate whether overexpression of KLF5 could enhance the cardioprotective characteristics of BMSCs, particularly in terms of mitigating structural and electrical remodeling. Our in vivo experiments revealed that transplantation of KLF5-overexpressing BMSCs in mice with MI led to a substantial reduction in ventricular fibrosis and the occurrence of ventricular arrhythmias (VAs). In vitro coculture experiments demonstrated that BMSCs could inhibit CFs activation and cytoskeleton protein bundling induced by hypoxia through paracrine effects, resulting in reduced expression of α-SMA and Collagen I. Furthermore, coculturing BMSCs significantly reduced the expression of connexin 43, alleviated hypoxia, increased the expression of inward-rectifier K+ current (Kir), and decreased voltage-dependent K+ (Kv) currents. Mechanistically, KLF5 enhanced the effects of BMSCs by facilitating the transfer of miR-152-3 p from BMSCs-derived exosomes to CFs. Overall, our findings show that BMSCs transplantation promotes the recovery of cardiac function and reduces the incidence of arrhythmias by inhibiting CFs activation and modulating CFs Kir current remodeling. Additionally, overexpression of KLF5 enhances the cardioprotective effects of BMSCs.
期刊介绍:
Stem Cells International is a peer-reviewed, Open Access journal that publishes original research articles, review articles, and clinical studies in all areas of stem cell biology and applications. The journal will consider basic, translational, and clinical research, including animal models and clinical trials.
Topics covered include, but are not limited to: embryonic stem cells; induced pluripotent stem cells; tissue-specific stem cells; stem cell differentiation; genetics and epigenetics; cancer stem cells; stem cell technologies; ethical, legal, and social issues.