Mechanism of Enhanced MerTK-Dependent Macrophage Efferocytosis by Extracellular Vesicles

Overview

Journal Arterioscler Thromb Vasc Biol

Date 2019 Aug 23

PMID 31434491

Citations 42

Authors

Geoffrey de Couto

Ervin Jaghatspanyan

Matthew DeBerge

Weixin Liu

Kristin Luther

Yizhou Wang

Jie Tang

Edward B Thorp

Eduardo Marban

Affiliations

Soon will be listed here.

Abstract

Objective: Extracellular vesicles secreted by cardiosphere-derived cells (CDC) polarize macrophages toward a distinctive phenotype with enhanced phagocytic capacity (M). These changes underlie cardioprotection by CDC 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 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. CDC exposure induces sustained MerTK expression in M through extracellular vesicle transfer of microRNA-26a (via suppression of ); the cardioprotective response is lost in animals deficient in MerTK. Single-cell RNA-sequencing revealed phagocytic pathway activation in M, with increased expression of complement factor , a phagocytosis facilitator.

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

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