Platelet derived small extracellular vesicles are cardioprotective in murine myocardial infarction

Abstract Ischaemic heart disease and myocardial infarction remain the leading causes of mortality worldwide. This occurs when a coronary artery becomes occluded, leading to ischaemic damage which can develop into heart failure. However, current treatments do not directly promote myocardial repair. Although platelets mediate the primary ischaemic damage, they also release numerous beneficial pro-reparative mediators including soluble factors and extracellular vesicles, sub-micron sized mediators of intercellular communication. This study aimed to assess the cardioprotective efficacy of these secretome elements. To this end, murine platelets were stimulated ex vivo to trigger secretion. The full releasate secretome was then segregated into its components: small- and large extracellular vesicle-enriched fractions, and extracellular vesicle-depleted molecular releasate. These were injected into the myocardium at the time of permanent coronary artery ligation in murine models of myocardial infarction. Injection of full releasate led to significantly better cardiac function compared with vehicle from 7d to 21d post infarct. This benefit was predominantly mediated by the small extracellular vesicle-enriched fraction that, when isolated and injected into the infarcting myocardium, successfully preserved cardiac function and enhanced tissue mural cell density. Thus, this study establishes platelet-derived small extracellular vesicles as promising therapeutic candidates for myocardial infarction which could harness the endogenous regenerative potential of platelets in clinic.