Systemic administration of induced pluripotent stem cell-derived mesenchymal stem cells improves cardiac function through extracellular vesicle-mediated tissue repair in a rat model of ischemic cardiomyopathy.

INTRODUCTION

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.