Therapeutic Potential of Hypoxia-Preconditioned hiPSC-Epicardial Cell-Derived Exosomes in Mice with Myocardial Infarction

BackgroundIt has been demonstrated that stem cell transplantation promotes healing of the infarcted heart through paracrine effects. However, the therapeutic potential of exosomes secreted by hiPSC-derived epicardial cells (hEP-Exos) for treating infarcted hearts remains unclear. Myocardial infarction (MI) can trigger EP activation, increasing EP paracrine function. Therefore, this study aims to determine and compare the cardioprotective effects of exosomes secreted by hEPs under normoxic (Exo-N) and hypoxic (Exo-H) conditions in MI mice and to explore the underlying mechanisms. MethodsTwo types of exosomes were collected by ultracentrifugation and delivered via intramyocardial injection in a murine MI model. The protective effects of Exo-N and Exo-H on the infarcted heart were assessed using echocardiography, histological examination, and immunofluorescence analysis. Additionally, microRNA sequencing, luciferase activity assays, and miRNA gain-and loss-of-function experiments were performed to identify enriched miRNAs and investigate their roles in different exosome populations. ResultsIn vitro, both Exo-N and Exo-H enhanced the migration and tube-formation capacities in human umbilical vein endothelial cells (HUVECs) and reduced the apoptosis in hiPSC-derived cardiomyocytes (hCMs) under oxygen-glucose deprivation (OGD), with Exo-H exhibiting a stronger effect. In vivo, both Exo-N and Exo-H significantly improved contractile function, reduced infarct size, and mitigated adverse remodeling in mouse hearts with MI, accompanied by increased cardiomyocyte survival and angiogenesis, with Exo-H showing superior efficacy. Mechanistically, miRNA sequencing revealed distinct cargo profiles between Exo-N and Exo-H. miR-214-3p was identified as a key mediator of the enhanced therapeutic potency of Exo-H. miR-214-3p promoted EC angiogenesis by suppressing vasohibin-1 and attenuated cardiomyocyte mitochondrial fission and apoptosis by suppressing mitochondrial elongation factor 2 (MIEF2). ConclusionsThis study demonstrates that administration of hEP-Exos, particularly Exo-H, provides robust cardioprotection by enhancing cardiomyocyte survival and angiogenesis, potentially mediated by miR-214-3p. These findings suggest that conditioned hEP-Exos could be a promising and effective acellular therapeutic option for treating MI.