Sca‐1+ cardiac fibroblasts promote development of heart failure |
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| Authors: | Guobao Chen William Bracamonte‐Baran Nicola L Diny Xuezhou Hou Monica V Talor Kai Fu Yue Liu Giovanni Davogustto Hernan Vasquez Heinrich Taegtmeyer O Howard Frazier Ari Waisman Simon J Conway Fengyi Wan Daniela Čiháková |
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| Institution: | 1. Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA;2. W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA;3. Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA;4. Department of Internal Medicine, Division of Cardiology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, USA;5. Texas Heart Institute, CHI St. Luke's Health ‐ Baylor St. Luke's Medical Center, Houston, TX, USA;6. Institute for Molecular Medicine, University of Mainz, Mainz, Germany;7. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA;8. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA |
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| Abstract: | The causative effect of GM‐CSF produced by cardiac fibroblasts to development of heart failure has not been shown. We identified the pathological GM‐CSF‐producing cardiac fibroblast subset and the specific deletion of IL‐17A signaling to these cells attenuated cardiac inflammation and heart failure. We describe here the CD45?CD31?CD29+mEF‐SK4+PDGFRα+Sca‐1+periostin+ (Sca‐1+) cardiac fibroblast subset as the main GM‐CSF producer in both experimental autoimmune myocarditis and myocardial infarction mouse models. Specific ablation of IL‐17A signaling to Sca‐1+periostin+ cardiac fibroblasts (PostnCreIl17rafl/fl) protected mice from post‐infarct heart failure and death. Moreover, PostnCreIl17rafl/fl mice had significantly fewer GM‐CSF‐producing Sca‐1+ cardiac fibroblasts and inflammatory Ly6Chi monocytes in the heart. Sca‐1+ cardiac fibroblasts were not only potent GM‐CSF producers, but also exhibited plasticity and switched their cytokine production profiles depending on local microenvironments. Moreover, we also found GM‐CSF‐positive cardiac fibroblasts in cardiac biopsy samples from heart failure patients of myocarditis or ischemic origin. Thus, this is the first identification of a pathological GM‐CSF‐producing cardiac fibroblast subset in human and mice hearts with myocarditis and ischemic cardiomyopathy. Sca‐1+ cardiac fibroblasts direct the type of immune cells infiltrating the heart during cardiac inflammation and drive the development of heart failure. |
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| Keywords: | GM‐CSF Heart failure IL‐17 Fibroblasts Myocarditis |
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