RRC ID 65870
Author Nakaya M, Watari K, Tajima M, Nakaya T, Matsuda S, Ohara H, Nishihara H, Yamaguchi H, Hashimoto A, Nishida M, Nagasaka A, Horii Y, Ono H, Iribe G, Inoue R, Tsuda M, Inoue K, Tanaka A, Kuroda M, Nagata S, Kurose H.
Title Cardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarction.
Journal J Clin Invest
Abstract Myocardial infarction (MI) results in the generation of dead cells in the infarcted area. These cells are swiftly removed by phagocytes to minimize inflammation and limit expansion of the damaged area. However, the types of cells and molecules responsible for the engulfment of dead cells in the infarcted area remain largely unknown. In this study, we demonstrated that cardiac myofibroblasts, which execute tissue fibrosis by producing extracellular matrix proteins, efficiently engulf dead cells. Furthermore, we identified a population of cardiac myofibroblasts that appears in the heart after MI in humans and mice. We found that these cardiac myofibroblasts secrete milk fat globule-epidermal growth factor 8 (MFG-E8), which promotes apoptotic engulfment, and determined that serum response factor is important for MFG-E8 production in myofibroblasts. Following MFG-E8-mediated engulfment of apoptotic cells, myofibroblasts acquired antiinflammatory properties. MFG-E8 deficiency in mice led to the accumulation of unengulfed dead cells after MI, resulting in exacerbated inflammatory responses and a substantial decrease in survival. Moreover, MFG-E8 administration into infarcted hearts restored cardiac function and morphology. MFG-E8-producing myofibroblasts mainly originated from resident cardiac fibroblasts and cells that underwent endothelial-mesenchymal transition in the heart. Together, our results reveal previously unrecognized roles of myofibroblasts in regulating apoptotic engulfment and a fundamental importance of these cells in recovery from MI.
Volume 127(1)
Pages 383-401
Published 2017-1-3
DOI 10.1172/JCI83822
PII 83822
PMID 27918308
PMC PMC5199696
MeSH Animals Antigens, Surface / genetics Antigens, Surface / metabolism* Apoptosis* Cell Survival / genetics Epithelial-Mesenchymal Transition* Male Mice Mice, Knockout Milk Proteins / genetics Milk Proteins / metabolism* Myocardial Infarction / genetics Myocardial Infarction / metabolism* Myocardial Infarction / pathology Myocardium / metabolism* Myocardium / pathology Myofibroblasts / metabolism* Myofibroblasts / pathology
IF 11.864
Human and Animal Cells L929