Metabolic Remodeling during Early Cardiac Lineage Specification of Pluripotent Stem Cells

Growing evidence indicates that metabolites and energy metabolism play an active rather than consequential role in regulating cellular fate. Cardiac development requires dramatic metabolic remodeling from relying primarily on glycolysis in pluripotent stem cells (PSCs) to oxidizing a wide array of energy substrates to match the high bioenergetic demands of continuous contraction in the developed heart. However, a detailed analysis of how remodeling of energy metabolism contributes to human cardiac development is lacking. Using dynamic multiple reaction monitoring metabolomics of central carbon metabolism, we evaluated temporal changes in energy metabolism during human PSC 3D cardiac lineage specification. Significant metabolic remodeling occurs during the complete differentiation, yet temporal analysis revealed that most changes occur during transitions from pluripotency to mesoderm (day 1) and mesoderm to early cardiac (day 5), with limited maturation of cardiac metabolism beyond day 5. Real-time metabolic analysis demonstrated that while hPSC cardiomyocytes (hPSC-CM) showed elevated rates of oxidative metabolism compared to PSCs, they still retained high glycolytic rates, confirming an immature metabolic phenotype. These observations support the opportunity to metabolically optimize the differentiation process to support lineage specification and maturation of hPSC-CMs.

Automated summary

Growing evidence suggests that metabolites and energy metabolism have an active role in regulating cellular fate, particularly in cardiac development. A study on human pluripotent stem cells (PSCs) reveals significant metabolic remodeling during cardiac lineage specification, with most changes occurring during transitions from pluripotency to mesoderm and mesoderm to early cardiac stages. The findings highlight the opportunity to optimize metabolism during differentiation to support the specification and maturation of human PSC-derived cardiomyocytes.