期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 127, 期 1, 页码 383-401出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI83822
关键词
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资金
- Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT) [25713007, 25253011]
- MEXT [15H01383, 22136008]
- Kyushu University Interdisciplinary Programs in Education and Projects in Research Development (PP)
- Japan Heart Foundation/Novartis Grant for Research Award on Molecular and Cellular Cardiology
- Takeda Science Foundation
- Naito Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Suzuken Memorial Foundation
- Astellas Foundation for Research on Metabolic Disorders
- Kanae Foundation for the Promotion of Medical Science
- Kaibara Morikazu Medical Science Promotion Foundation
- MSD Life Science Foundation
- Nakajima Foundation
- Platform Project for Supporting Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Structural Life Science)
- Japan Agency for Medical Research and development (AMED)
- Funding Program for Next Generation World-Leading Researchers (NEXT Program)
- Grants-in-Aid for Scientific Research [22136008, 15H01383, 15H05785, 17H01525, 16K08718, 25713007, 25253011, 16J03451] Funding Source: KAKEN
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.
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