Mechanism of Enhanced MerTK-Dependent Macrophage Efferocytosis by Extracellular Vesicles

Authors: Geoffrey de Couto, Ervin Jaghatspanyan, Matthew DeBerge, Weixin Liu, Kristin Luther, Yizhou Wang, Jie Tang, Edward B. Thorp, Eduardo Marbán - Arteriosclerosis Thrombosis and Vascular Biology 2019 cited by 84

Objective: 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. 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 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. Conclusions: Together, these data demonstrate that extracellular vesicle modulation of MerTK and C1qa expression leads to enhanced macrophage efferocytosis and cardioprotection.