Single-cell analysis of human iPSC-derived multi-lineage mini-cardiac organoid reveals molecular pathways to promote cardiomyocyte maturation and heart repair

ABSTRACT: Human induced pluripotent stem cell (hiPSC)-derived cardiovascular cells are promising cell source for cell therapy to repair the heart. Cardiac microtissue consisted of cardiomyocytes and fibroblast cells exhibited much better physiological functions. How different cardiovascular cell types interact and evolve in 3D microenvironment is unknown. In this study, we performed single-cell transcriptome profiling of hiPSC-derived mini-cardiac organoid consisted of cardiomyocytes, endothelial cells and smooth muscle cells. Our analysis showed that cardiac fibroblasts emerged spontaneously in 3D microenvironment which in turn facilitated the maturation of cardiomyocytes. HiPSC-derived cardiomyocytes, endothelial cells and smooth muscle cells assembled into mini-cardiac organoid in collagen-matrigel after 2 weeks. Single-cell study uncovered significant cell fate shift and improvement in cardiomyocyte maturation status upon-multilineage co-culture. Ligand-receptor analysis identified DLK1-Notch signaling to be one of the most upregulated pathways in the fibroblast population. Modulate the activity of DLK1-Notch signaling affected the assembly of the mini-cardiac organoid and the expression of immune regulatory genes. Interestingly, transplantation of trilineage mini-cardiac organoid into a rat model of myocardial infarction leads to significant improvement of cardiac function. Collectively, our single-cell analysis of mini-cardiac organoid provided rich information about cell fate dynamics and multilineage cross-talks occurred in the 3D microenvironment, which bring new insight on the molecular mechanism that promotes cardiomyocyte maturation and heart repair.

ORGANISM(S): Homo sapiens

PROVIDER: GSE166462 | GEO | 2023/02/09

REPOSITORIES: GEO