INVESTIGATING THE UNDERLYING MOLECULAR MECHANISM GOVERNING MATURATION AND DISEASE PROGRESSION USING HUMAN EMBRYONIC STEM CELL DERIVED CARDIOMYOCYTES

Abstract

The immature characteristics and metabolic phenotypes of human pluripotent stem cell-derived cardiomyocytes restrict their applications for disease modelling, drug discovery and cell-based therapy. Leveraging on the metabolic shifts from glycolysis to fatty acid oxidation as CMs mature, a human hexokinase1-GFP metabolic reporter cell line was generated to facilitate the isolation of fetal or relatively more matured hPSC-CMs. RNA sequencing uncovered a potential role of interferon signalling pathway in regulating CM maturation. While several studies have underscored the importance of generating matured hPSC-derived CMs, these CMs were obtained using a 2D culture environment, their potentials in modelling more complex diseases, such as cardiac hypertrophy, have been demonstrated to be restricted. Herein, we reported successful generation of intrinsically formed human chambered cardiac organoids (CCOs) and highlighted their improved utility in modelling cardiac hypertrophy. Single cell transcriptomic profiling of CCOs established appropriate composition of cardiovascular cell types within the CCOs, and also demonstrated improved maturation of resident cardiomyocytes.