Endothelial progenitor cell-derived exosomes facilitate vascular endothelial cell repair through shuttling miR-21-5p to modulate Thrombospondin-1 expression

BACKGROUND: Our previous studies observed that administration of exosomes from endothelial progenitor cell (EPC) facilitated vascular repair in rat model of balloon injury. However, the molecular events underling this process remain elusive. Here, we aim to interrogate the key miRNA within EPC derived exosomes (EPC-exosomes) responsible for the activation of endothelial cell (EC) repair. METHODS: The efficacy of EPC-exosomes in reendothelialization was examined by Evans blue dye and histological examination in rat model of balloon-induced carotid artery injury. The effects of EPC-exosomes on human vascular endothelial cell (HUVEC) were also studied by evaluating the effects on growth, migratory and tube-formation. To dissect the underlying mechanism, RNA-sequencing assays were performed to determine miRNA abundance in exosomes and mRNA profiles in exosomes-treated HUVEC. Meanwhile, in vitro loss of function assays identified an exosomal miRNA and its target gene in EC, which engaged in EPC-exosomes-induced EC repair. RESULTS: Administration of EPC-exosomes potentiated reendothelialization in the early phase after endothelial damage in the rat carotid artery. The uptake of exogenous EPC-exosomes intensified HUVEC in proliferation rate, migratory and tube-forming ability. Integrative analyses of miRNA-mRNA interactions revealed that miR-21-5p was highly enriched in EPC-exosomes and specifically suppressed the expression of an angiogenesis inhibitor Thrombospondin-1 (THBS1) in the recipient EC. The following functional studies demonstrated a fundamental role of miR-21-5p in the pro-angiogenic activities of EPC-exosomes. CONCLUSIONS: The present work highlights a critical event for the regulation of EC behavior by EPC-exosomes, which EPC-exosomes may deliver miR-21-5p and inhibit THBS1 expression to promote endothelial cell repair.