Single cell study of cellular diversity and mutual communication in chronic heart failure and drug repositioning

Abstract

Non-cardiomyocytes (non-CMs) play an important role in the process of cardiac remodeling of chronic heart failure. The mechanism of non-CMs transit and interact with each other remains largely unknown. Here, we try to characterize the cellular landscape of non-CMs in mice with chronic heart failure by using single-cell RNA sequencing (scRNA-seq) and provide potential therapeutic hunts. Cellular and molecular analysis revealed that the most affected cellular types are mainly fibroblasts and endothelial cells. Specially, Fib_0 cluster, the most abundant cluster in fibroblasts, was the only increased one, enriched for collagen synthesis genes such as Adamts4 and Crem, which might be responsible for the fibrosis in cardiac remodeling. End_0 cluster in endothelial cells was also the most abundant and only increased one, which has an effect of blood vessel morphogenesis. Cell communication further confirmed that fibroblasts and endothelial cells are the driving hubs in chronic heart failure. Furthermore, using fibroblasts and endothelial cells as the entry point of CMap technology, histone deacetylation (HDAC) inhibitors and HSP inhibitors were identified as potential anti-heart failure new drugs, which should be evaluated in the future. The combined application of scRNA-seq and CMap might be an effective way to achieve drug repositioning.