Failing heart-specific cardiac fibroblasts induce heart failure via c-Myc Expansion [snRNA-seq]

Heart failure (HF) is a major global problem with increasing numbers of patients and deaths in many countries. Existing studies on HF have focused primarily on cardiomyocytes, with few studies targeting non-cardiomyocytes. This study focused on cardiac fibroblasts (CFs) as a cause of HF. Single-cell RNA sequencing of mouse hearts revealed six distinct subclusters of CFs at various stages after pressure overload, with one subcluster being specific to the HF stage. The transcription factor c-Myc is specifically expressed in HF-specific CFs. CFs-specific deletion of c-Myc ameliorates pressure overload-induced cardiac dysfunction without affecting fibrosis. The chemokine Cxcl1 is highly expressed in HF-specific CFs and downregulated in CFs-specific c-Myc knockout mice. Chromatin immunoprecipitation analysis revealed that c-Myc binds to the promoter region of Cxcl1 in CFs. Cxcr2, the receptor for Cxcl1, is expressed in cardiomyocytes, and blockade of the Cxcl1-Cxcr2 signalling pathway prevents pressure overload-induced cardiac dysfunction. The addition of CXCL1 reduces the contractility of cardiomyocytes of neonatal rats and human iPS-derived cardiomyocyte organoids. Human CFs from failing hearts expressed c-MYC and CXCL1, while CFs from control hearts did not. These findings suggest that HF-specific CFs play an important role in inducing HF by upregulating c-Myc and Cxcl1 and that CFs could be a novel therapeutic target for HF.