Precision Intervention of Cardiac Remodeling Based on Cellular Composition Principles Uncovered by Single-Cell Transcriptomics

Stress-induced cardiac remodeling forms the foundation of many cardiac diseases, yet little is known about the spatiotemporal interplay amongst cell types underlying the pathological progression of the heart from normal to a diseased state, at single-cell resolution. Here, we analyzed 11,492 single cells, including both cardiomyocytes (CMs) and non-cardiomyocytes (NCMs), at different stages in a mouse model of pressure overload-induced cardiac remodeling, and identified a full list of factors and signaling pathways important for disease progression. Through constructing cell crosstalk maps, we revealed sequential switching in NCM subtype (fibroblasts, macrophages, and endothelial cells) utilization at different stages of cardiac remodeling. Intriguingly, stage-specific pharmacological inhibition of macrophage subtype switch dramatically retarded heart transition from adaptive to a maladaptive state. Consistently, alterations of cardiac remodeling related-genes were highly conserved in human samples. Together, our study not only characterizes the molecular features of different cell types and identifies crucial factors underlying cardiac remodeling, but may also have important implications for stage- and cell type-specific precise intervention in cardiac diseases.