Lipid Metabolism Remodeling in Human Cardiomyocyte Differentiation and Maturation

During cardiac development, metabolic remodeling is characterized by a transition from glycolysis-dependent energy production to reliance on fatty acid oxidation. Lipids function as essential energy substrates and structural components throughout cardiac formation and maturation. However, the dynamic changes in endogenous lipid species during human cardiac development remain incompletely elucidated. In this study, we delineated distinct lipidomic profiles of human embryonic stem cells (ESCs), mesoderm (MES), cardiac progenitors (CPCs), immature cardiomyocytes (CMs), and mature CMs derived from ESCs using high-performance liquid chromatography (HPLC). Notably, ceramide concentrations peaked at the CPC stage, suggesting a pivotal role in mediating the MES-to-CPCs transition. Concurrently, lipid metabolites including GM3, phosphatidylcholine (PC), lysophosphatidylcholine (LPC), and lysophosphatidic acid (LPA) were significantly upregulated in mature CMs. Integrative transcriptomic and chromatin accessibility analyses further refined the landscape of lipid remodeling during CM differentiation. Functional assays demonstrated that LPA enhances the stability of the beating rhythm in CPCs, while both PC and LPA facilitate CM maturation. Collectively, our findings establish a comprehensive and dynamic lipidomic atlas of human cardiogenesis, providing a novel framework to advance the understanding of lipid-mediated regulatory mechanisms in human heart development.