title: Cardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarction.
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.
authors.forename: Michio
authors.initials: M
authors.lastname: Nakaya
authors.forename: Kenji
authors.initials: K
authors.lastname: Watari
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Tajima
authors.forename: Takeo
authors.initials: T
authors.lastname: Nakaya
authors.forename: Shoichi
authors.initials: S
authors.lastname: Matsuda
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ohara
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nishihara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Akiko
authors.initials: A
authors.lastname: Hashimoto
authors.forename: Mitsuho
authors.initials: M
authors.lastname: Nishida
authors.forename: Akiomi
authors.initials: A
authors.lastname: Nagasaka
authors.forename: Yuma
authors.initials: Y
authors.lastname: Horii
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ono
authors.forename: Gentaro
authors.initials: G
authors.lastname: Iribe
authors.forename: Ryuji
authors.initials: R
authors.lastname: Inoue
authors.forename: Makoto
authors.initials: M
authors.lastname: Tsuda
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Inoue
authors.forename: Akira
authors.initials: A
authors.lastname: Tanaka
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kuroda
authors.forename: Shigekazu
authors.initials: S
authors.lastname: Nagata
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kurose
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D002470:Cell Survival / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008894:Milk Proteins / Q000235:genetics / Q000378:metabolism*; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D058628:Myofibroblasts / Q000378:metabolism* / Q000473:pathology
chemical_list: D000954:Antigens, Surface; C490919:Mfge8 protein, mouse; D008894:Milk Proteins