Sca-1+ cardiac fibroblasts promote development of heart failure

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(+)PDGFR(+)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 (Postn(Cre)Il17ra(fl/fl)) protected mice from post-infarct heart failure and death. Moreover, Postn(Cre)Il17ra(fl/fl) mice had significantly fewer GM-CSF-producing Sca-1(+) cardiac fibroblasts and inflammatory Ly6C(hi) 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.