Lipid Metabolism Remodeling in Human Cardiomyocyte Differentiation and Maturation

During early cardiac development, metabolic remodeling gradually switches from glycolysis-dependent energy production to fatty acid oxidation. Lipids serve as crucial energy substrates and structural components throughout heart formation and maturation. However, dynamic remodeling in endogenous lipid species during human cardiac development remains poorly characterized. In this study, we systematically performed high-coverage lipidomic profiling across five consecutive developmental stages, including human embryonic stem cells (ESCs), mesoderm (MES), cardiac progenitors (CPCs), immature cardiomyocytes (CMs), and mature CMs derived from human ESCs using high-performance liquid chromatography. Ceramide levels peaked at the CPC stage, implicating a key role in the MES-to-CPC lineage transition. Meanwhile, lipid metabolites such as monosialodihexosylganglioside (GM3), phosphatidylcholine (PC), lysophosphatidylcholine (LPC), and lysophosphatidic acid (LPA) were markedly elevated in mature CMs. Integrated transcriptomic and chromatin accessibility analyses further delineated the temporal regulatory landscape underlying stage-dependent lipid remodeling during cardiogenic differentiation. Functional assays revealed that PC promotes the expression of mature CM marker genes and improves the CM viability. Collectively, these findings establish a comprehensive, high-resolution dynamic lipidomic atlas of human cardiogenesis, providing valuable insights for understanding lipid-mediated regulatory mechanisms in heart development.