Sca‐1⁺ cardiac fibroblasts promote development of heart failure

Abstract

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 ( 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.