Sca‐1⁺ cardiac fibroblasts promote development of heart failure

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.