Dual genetic tracing reveals a unique fibroblast subpopulation modulating cardiac fibrosis
Creators
- 1. School of Life Science and Technology, ShanghaiTech University, Shanghai, China
- 2. State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China
- 3. Department of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- 4. School of Life Sciences, Westlake University, Hangzhou, China
- 5. Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
- 6. CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, China
- 7. Shanghai Laboratory Animal Research Center, Shanghai, China
- 8. Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
- 9. The Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China
- 10. Division of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- 11. Zhejiang Children's Hospital, Zhejiang University, Hangzhou, China
- 12. Department of Chemical Pathology; and Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
Description
After severe heart injury, fibroblasts are activated and proliferate excessively to form scar, leading to decreased cardiac function and eventually heart failure. It is unknown, however, whether cardiac fibroblasts are heterogeneous in respect of their degree of activation, proliferation, and function during cardiac fibrosis. Here, by dual recombinases-mediated genetic lineage tracing, we found that endocardium-derived fibroblasts (EndoFb) preferentially proliferate and expand in response to pressure overload. Fibroblast-specific proliferation tracing revealed highly regional expansion of activated fibroblasts after injury, the pattern of which mirrors that of EndoFb distribution in the heart. Specific ablation of EndoFb alleviates cardiac fibrosis and reduces the decline of heart function after pressure overload injury. Mechanistically, Wnt signaling promotes activation and expansion of EndoFb during cardiac remodeling. Our study identified EndoFb as a key fibroblast subpopulation accounting for severe cardiac fibrosis after pressure overload injury, and as a potential therapeutic target against cardiac fibrosis.
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