(W1341) INDUCED PLURIPOTENT STEM CELL-DERIVED MESENCHYMAL STEM CELLS IMPROVE CARDIAC FUNCTION THROUGH EXTRACELLULAR VESICLE-MEDIATED TISSUE REPAIR IN A RAT ISCHEMIC CARDIOMYOPATHY MODEL
Abstract: Induced pluripotent stem cell-derived mesenchymal stem cells (iPS-MSCs) are a novel type of stem cell which have a therapeutic effect on various diseases. Allogeneic iPS-MSCs are expected to be ideal cell sources because of their consistent quality and ability to avoid immune rejection. 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. We developed a rat ICM model by left anterior descending coronary artery ligation. iPS-MSCs were administered intravenously every week for four weeks in the iPS-MSC group, and Alix-knockdown iPS-MSCs in which Alix, a protein involved in the biogenesis of EVs, was knocked down by siRNA, were administered to the siAlix group. Left ventricular ejection fraction (LVEF) was significantly improved in the iPS-MSC group compared with that in the control of sham operation 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 a 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. Our study revealed that 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.
