Kawasumi Ryo, Kawamura Takuji, Yamashita Kizuku, Tominaga Yuji, Harada Akima, Ito Emiko, Takeda Maki, Kita Shunbun, Shimomura Iichiro, Miyagawa Shigeru
Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan.
Regen Ther. 2024 Dec 31;28:253-261. doi: 10.1016/j.reth.2024.12.008. eCollection 2025 Mar.
Systemic administration of induced pluripotent stem cell-derived mesenchymal stem cells (iPS-MSCs) has a therapeutic effect on myocardial ischemia. However, the therapeutic mechanism underlying systemic iPS-MSC-based therapy for ischemic cardiomyopathy (ICM) remains unclear. We investigated the therapeutic effects of iPS-MSCs through extracellular vesicle (EV)-mediated tissue repair in a rat model of ICM.
A rat ICM model was created by left anterior descending coronary artery ligation. iPS-MSCs were administered intravenously every week for four weeks in the iPS-MSC group, whereas saline was administered to the control group. Alix, a protein involved in the biogenesis of EVs, was knocked down, and Alix-knockdown iPS-MSCs were administered to the siAlix group. We analyzed sequential cardiac function using echocardiography, histological analysis, cell tracking analysis with fluorescent dyes, and comprehensive RNA sequencing of the border zone of the myocardium after treatment.
Left ventricular ejection fraction (LVEF) was significantly improved in the iPS-MSC group compared with that in the control group. In the siAlix group, LVEF was significantly lower than that in the iPS-MSC group. Histological analysis showed a significant decrease in fibrosis area and significant increase in microvascular density in the iPS-MSC group. A cell-tracking assay revealed iPS-MSC accumulation in the border zone of the myocardium during the acute phase. Comprehensive microRNA sequencing analysis revealed that EVs from iPS-MSCs contained miRNAs associated with anti-fibrosis and angiogenesis. Gene ontology analysis of differentially expressed genes in myocardial tissue also showed upregulation of pathways related to antifibrosis and neovascularization and downregulation of pathways linked to inflammation and T-cell differentiation.
Systemic administration of iPS-MSCs improved cardiac function through EV-mediated angiogenetic and antifibrotic effects in an ICM, suggesting the clinical possibility of treating chronic heart failure.
诱导多能干细胞来源的间充质干细胞（iPS-MSCs）的全身给药对心肌缺血具有治疗作用。然而，基于iPS-MSCs的全身治疗缺血性心肌病（ICM）的治疗机制仍不清楚。我们在ICM大鼠模型中研究了iPS-MSCs通过细胞外囊泡（EV）介导的组织修复的治疗效果。
通过结扎左冠状动脉前降支建立大鼠ICM模型。iPS-MSC组每周静脉注射iPS-MSCs，持续四周，而对照组注射生理盐水。敲低参与EV生物发生的蛋白质Alix，并将Alix敲低的iPS-MSCs注射到siAlix组。我们使用超声心动图、组织学分析、荧光染料细胞追踪分析以及治疗后心肌边界区的综合RNA测序来分析连续的心脏功能。
与对照组相比，iPS-MSC组的左心室射血分数（LVEF）显著提高。在siAlix组中，LVEF显著低于iPS-MSC组。组织学分析显示，iPS-MSC组的纤维化面积显著减少，微血管密度显著增加。细胞追踪试验显示，急性期iPS-MSCs在心肌边界区积聚。综合微小RNA测序分析显示，iPS-MSCs来源的EVs含有与抗纤维化和血管生成相关的微小RNA。心肌组织中差异表达基因的基因本体分析也显示，与抗纤维化和新血管形成相关的通路上调，与炎症和T细胞分化相关的通路下调。
iPS-MSCs的全身给药通过EV介导的血管生成和抗纤维化作用改善了ICM的心脏功能，提示了治疗慢性心力衰竭的临床可能性。
