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Cardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarction
Michio Nakaya, … , Shigekazu Nagata, Hitoshi Kurose
Michio Nakaya, … , Shigekazu Nagata, Hitoshi Kurose
Published December 5, 2016
Citation Information: J Clin Invest. 2017;127(1):383-401. https://doi.org/10.1172/JCI83822.
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Research Article Cardiology Inflammation

Cardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarction

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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

Michio Nakaya, Kenji Watari, Mitsuru Tajima, Takeo Nakaya, Shoichi Matsuda, Hiroki Ohara, Hiroaki Nishihara, Hiroshi Yamaguchi, Akiko Hashimoto, Mitsuho Nishida, Akiomi Nagasaka, Yuma Horii, Hiroki Ono, Gentaro Iribe, Ryuji Inoue, Makoto Tsuda, Kazuhide Inoue, Akira Tanaka, Masahiko Kuroda, Shigekazu Nagata, Hitoshi Kurose

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Figure 1

Cardiac myofibroblasts engulf dead cells ex vivo.

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Cardiac myofibroblasts engulf dead cells ex vivo.
(A) Ex vivo phagocytos...
(A) Ex vivo phagocytosis assay of apoptotic cells. Cardiac macrophages and myofibroblasts isolated from WT mice that underwent MI were exposed to apoptotic cells (green) (n = 3). The numbers of engulfed apoptotic cells per cardiac macrophage (Mac) and myofibroblast (Myo) are shown. Images were taken at 12–15 randomly selected fields. Arrows indicate engulfed apoptotic cells. Scale bar: 100 μm. Original magnification, ×40. (B) mRNA expression levels of Il6 or Tgfb1 in myofibroblasts treated with LPS after apoptotic engulfment. Cardiac myofibroblasts cocultured with (+) or without (−) apoptotic thymocytes (Apo) for 2 hours were treated with (+) or without (−) LPS at 1 μg/ml for 24 hours (n = 4). (C) αSMA-positive myofibroblasts did not express CD45. The cells collected from infarcted mouse hearts as myofibroblasts were harvested by treatment with accutase and immediately stained with antibodies for αSMA and CD45. Error bars represent the mean ± SEM. (A) **P < 0.01, unpaired 2-tailed Student’s t test. (B) ***P < 0.001, 1-way ANOVA followed by Newman-Keuls analysis.
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