Extracellular vesicles secreted by cardiosphere-derived cells (CDC_ev) polarize macrophages toward a distinctive phenotype with enhanced phagocytic capacity (M_CDCev). These changes underlie cardioprotection by CDC_ev 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 M_CDCev are especially effective at scavenging debris from dying cells (ie, efferocytosis) to attenuate irreversible damage post-myocardial infarction.

In vitro efferocytosis assays with bone marrow-derived macrophages, and in vivo transgenic rodent models of myocardial infarction, demonstrate enhanced apoptotic cell clearance with M_CDCev. CDC_ev exposure induces sustained MerTK expression in M_CDCev 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 M_CDCev, 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.