Y <scp>RNA</scp> fragment in extracellular vesicles confers cardioprotection via modulation of <scp>IL</scp> ‐10 expression and secretion

Abstract

Cardiosphere-derived cells (CDCs) reduce myocardial infarct size via secreted extracellular vesicles (CDC-EVs), including exosomes, which alter macrophage polarization. We questioned whether short non-coding RNA species of unknown function within CDC-EVs contribute to cardioprotection. The most abundant RNA species in CDC-EVs is a Y RNA fragment (EV-YF1); its relative abundance in CDC-EVs correlates with CDC potency <i>in vivo</i> Fluorescently labeled EV-YF1 is actively transferred from CDCs to target macrophages via CDC-EVs. Direct transfection of macrophages with EV-YF1 induced transcription and secretion of IL-10. When cocultured with rat cardiomyocytes, EV-YF1-primed macrophages were potently cytoprotective toward oxidatively stressed cardiomyocytes through induction of IL-10. <i>In vivo,</i> intracoronary injection of EV-YF1 following ischemia/reperfusion reduced infarct size. A fragment of Y RNA, highly enriched in CDC-EVs, alters <i>Il10</i> gene expression and enhances IL-10 protein secretion. The demonstration that EV-YF1 confers cardioprotection highlights the potential importance of diverse exosomal contents of unknown function, above and beyond the usual suspects (e.g., microRNAs and proteins).