Chen, GuobaoBracamonte-Baran, WilliamDiny, Nicola L.Hou, XuezhouTalor, Monica V.Fu, KaiLiu, YueDavogustto, GiovanniVasquez, HernanTaegtmeyer, HeinrichFrazier, O. HowardWaisman, AriConway, Simon J.Wan, FengyiČiháková, Daniela2019-12-192019-12-192018-09Chen, G., Bracamonte-Baran, W., Diny, N. L., Hou, X., Talor, M. V., Fu, K., … Čiháková, D. (2018). Sca-1+ cardiac fibroblasts promote development of heart failure. European journal of immunology, 48(9), 1522–1538. doi:10.1002/eji.201847583https://hdl.handle.net/1805/21510The 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+mEFSK4+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 fibrob-lasts 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 GMCSF-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 GMCSF-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.en-USPublisher PolicyGM-CSFHeart failureIL-17FibroblastsMyocarditisArticle