期刊
NATURE MEDICINE
卷 19, 期 8, 页码 1047-1054出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.3218
关键词
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资金
- US National Institutes of Health (NIH) [DK55001, DK81976, CA125550, CA155370, CA163191, CA151925]
- Cancer Prevention and Research Institute of Texas
- Metastasis Research Center at MD Anderson Cancer Center
- NIH [2T32DK007760-11, 5T32HL007374-30, T32DK007726, 5F32DK082119-02]
- US Department of Defense Breast Cancer Research [W81XWH-09-1-0008]
- International Society of Nephrology Fellowship
Myofibroblasts are associated with organ fibrosis, but their precise origin and functional role remain unknown. We used multiple genetically engineered mice to track, fate map and ablate cells to determine the source and function of myofibroblasts in kidney fibrosis. Through this comprehensive analysis, we identified that the total pool of myofibroblasts is split, with 50% arising from local resident fibroblasts through proliferation. The nonproliferating myofibroblasts derive through differentiation from bone marrow (35%), the endothelial-to-mesenchymal transition program (10%) and the epithelial-to-mesenchymal transition program (5%). Specific deletion of Tgfbr2 in alpha-smooth muscle actin (alpha SMA)(+) cells revealed the importance of this pathway in the recruitment of myofibroblasts through differentiation. Using genetic mouse models and a fate-mapping strategy, we determined that vascular pericytes probably do not contribute to the emergence of myofibroblasts or fibrosis. Our data suggest that targeting diverse pathways is required to substantially inhibit the composite accumulation of myofibroblasts in kidney fibrosis.
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