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 Benjamin Thorp, Eduardo Marbán

Research output: Contribution to journalArticle

1 Citation (Scopus)

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
StatePublished - Oct 1 2019

Fingerprint

Macrophages
Myocardial Infarction
No-Reflow Phenomenon
RNA Sequence Analysis
Centers for Disease Control and Prevention (U.S.)
MicroRNAs
Phagocytosis
Rodentia
Phenotype
Extracellular Vesicles

Keywords

  • extracellular vesicles
  • macrophages
  • myocardial infarction
  • phagocytosis
  • phenotype

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

de Couto, Geoffrey ; Jaghatspanyan, Ervin ; DeBerge, Matthew ; Liu, Weixin ; Luther, Kristin ; Wang, Yizhou ; Tang, Jie ; Thorp, Edward Benjamin ; Marbán, Eduardo. / Mechanism of Enhanced MerTK-Dependent Macrophage Efferocytosis by Extracellular Vesicles. In: Arteriosclerosis, thrombosis, and vascular biology. 2019 ; Vol. 39, No. 10. pp. 2082-2096.
@article{8ef8dc16cfdd45aab0c5b71e1d18fc9e,
title = "Mechanism of Enhanced MerTK-Dependent Macrophage Efferocytosis by Extracellular Vesicles",
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.",
keywords = "extracellular vesicles, macrophages, myocardial infarction, phagocytosis, phenotype",
author = "{de Couto}, Geoffrey and Ervin Jaghatspanyan and Matthew DeBerge and Weixin Liu and Kristin Luther and Yizhou Wang and Jie Tang and Thorp, {Edward Benjamin} and Eduardo Marb{\'a}n",
year = "2019",
month = "10",
day = "1",
doi = "10.1161/ATVBAHA.119.313115",
language = "English (US)",
volume = "39",
pages = "2082--2096",
journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",
issn = "1079-5642",
publisher = "Lippincott Williams and Wilkins",
number = "10",

}

Mechanism of Enhanced MerTK-Dependent Macrophage Efferocytosis by Extracellular Vesicles. / de Couto, Geoffrey; Jaghatspanyan, Ervin; DeBerge, Matthew; Liu, Weixin; Luther, Kristin; Wang, Yizhou; Tang, Jie; Thorp, Edward Benjamin; Marbán, Eduardo.

In: Arteriosclerosis, thrombosis, and vascular biology, Vol. 39, No. 10, 01.10.2019, p. 2082-2096.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mechanism of Enhanced MerTK-Dependent Macrophage Efferocytosis by Extracellular Vesicles

AU - de Couto, Geoffrey

AU - Jaghatspanyan, Ervin

AU - DeBerge, Matthew

AU - Liu, Weixin

AU - Luther, Kristin

AU - Wang, Yizhou

AU - Tang, Jie

AU - Thorp, Edward Benjamin

AU - Marbán, Eduardo

PY - 2019/10/1

Y1 - 2019/10/1

N2 - 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.

AB - 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.

KW - extracellular vesicles

KW - macrophages

KW - myocardial infarction

KW - phagocytosis

KW - phenotype

UR - http://www.scopus.com/inward/record.url?scp=85072687385&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85072687385&partnerID=8YFLogxK

U2 - 10.1161/ATVBAHA.119.313115

DO - 10.1161/ATVBAHA.119.313115

M3 - Article

C2 - 31434491

AN - SCOPUS:85072687385

VL - 39

SP - 2082

EP - 2096

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

SN - 1079-5642

IS - 10

ER -