Single-cell analysis elucidates the mechanism underlying heart regeneration by in vivo direct cardiac reprogramming

Abstract

Cardiovascular disease is a leading cause of death worldwide. Because adult cardiomyocytes (CMs) have a low regenerative capacity, damaged CMs are replaced by cardiac fibroblasts (CFs) after myocardial infarction (MI), leading to loss of contractile function of the heart and eventually to heart failure. There are no treatments available to regenerate myocardium and reverse fibrosis in MI. Direct cardiac reprogramming may be a promising approach for both cardiac regeneration and antifibrotic therapy. Overexpression of cardiac transcription factors, including Mef2c, Gata4, Tbx5, and Hand2 (MGTH), directly reprograms a subset of CFs into induced cardiomyocytes (iCMs) in vivo and vitro. Recently, we found that in vivo cardiac reprogramming generates new iCMs from resident CFs, improves cardiac function, and reduces fibrosis in chronic MI in mice. Single-cell RNA sequencing (scRNA-seq) demonstrated that in vivo cardiac reprogramming altered the interstitial cell landscape in chronic MI. In addition, scRNA-seq revealed that overexpression of MGTH in CFs not only induced iCMs, but also suppressed fibroblast gene signatures through the conversion of profibrotic CFs to a quiescent antifibrotic state. These findings suggest that in vivo cardiac reprogramming may become a pioneering therapy for chronic HF by regenerating cardiomyocytes and reducing fibrosis.