Single-cell atlas of multilineage cardiac organoids derived from human induced pluripotent stem cells

Abstract Human induced pluripotent stem cell (hiPSC)-derived cardiac organoids can be used to model human heart development and cardiovascular disease, and provide therapeutic cells to repair the heart. We used single-cell transcriptome analysis to dissect the development of 3D mini-cardiac organoids (MCOs) consisting of hiPSC-derived cardiomyocytes, and endothelial and smooth muscle cells. We found that the 3D matrix-rich microenvironment significantly promoted the maturation of cardiomyocytes, and mixing endothelial and smooth muscle cells with cardiomyocytes led to the formation of cardiac fibroblast highly expressing DLK1. Modulation of DLK1 signaling affected immunomodulatory gene expression in 2D cultured cardiomyocytes. Transplantation of multilineage MCO into a rat model of myocardial infarction significantly improved cardiac function and reduced fibrosis in the infarcted area. Our single-cell analysis of MCO provided rich information about cell state and fate dynamics in the 3D multilineage microenvironment and brought new insight into the molecular mechanism that promotes cardiomyocyte maturation and heart repair.