Mechanism of Enhanced MerTK-Dependent Macrophage Efferocytosis by Extracellular Vesicles.

Abstract

Extracellular vesicles secreted by cardiosphere-derived cells (CDCev) polarize macrophages toward a distinctive phenotype with enhanced phagocytic capacity (MCDCev). These changes underlie cardioprotection by CDCev and by the parent CDCs, notably attenuating the no-reflow phenomenon following myocardial infarction, but the mechanisms are unclear. Here, we tested the hypothesis that MCDCev are especially effective at scavenging debris from dying cells (ie, efferocytosis) to attenuate irreversible damage post-myocardial infarction. Approach and Results: In vitro efferocytosis assays with bone marrow-derived macrophages, and in vivo transgenic rodent models of myocardial infarction, demonstrate enhanced apoptotic cell clearance with MCDCev. CDCev exposure induces sustained MerTK expression in MCDCev through extracellular vesicle transfer of microRNA-26a (via suppression of Adam17); the cardioprotective response is lost in animals deficient in MerTK. Single-cell RNA-sequencing revealed phagocytic pathway activation in MCDCev, with increased expression of complement factor C1qa, a phagocytosis facilitator. Together, these data demonstrate that extracellular vesicle modulation of MerTK and C1qa expression leads to enhanced macrophage efferocytosis and cardioprotection.