Mechanism of enhanced MerTK-Dependent macrophage efferocytosis by extracellular vesicles

Geoffrey De Couto*, Ervin Jaghatspanyan, Matthew Deberge, Weixin Liu, Kristin Luther, Yizhou Wang, Jie Tang, Edward B. Thorp, Eduardo Marbán

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)2082-2096
Number of pages15
JournalArteriosclerosis, thrombosis, and vascular biology
Volume39
Issue number10
DOIs
Publication statusPublished - Oct 1 2019

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Keywords

  • Extracellular vesicles
  • Macrophages
  • Myocardial infarction
  • Phagocytosis
  • Phenotype

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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