Cardiac reprogramming and Gata4 overexpression reduce fibrosis and improve diastolic dysfunction in heart failure with preserved ejection fraction [scRNA-seq]

Fibrosis is important pathogenesis in heart failure with preserved ejection fraction (HFpEF). We previously reported that the overexpression of cardiac transcription factors, Mef2c/Gata4/Tbx5/Hand2 (MGTH) could directly reprogram cardiac fibroblasts (CFs) into induced CMs (iCMs) and reduce fibrosis. Here we show that in vivo cardiac reprogramming generated iCMs from resident CFs, improved cardiac function, and reversed fibrosis in HFpEF model using a novel transgenic mouse system. scRNA-seq of non-cardiomyocytes revealed that cardiac reprogramming suppressed fibroblastic gene expression via conversion of profibrotic profile to a quiescent state. Thus, in vivo cardiac reprogramming may be a promising approach for HFpEF. Overall design: Hearts were harvested 15 weeks after the start of the experiment from three groups (Ctrl, Ctrl_HF, and TTg_HF) for scRNA-seq.