Fatty Acids Enhance the Maturation of Cardiomyocytes Derived from Human Pluripotent Stem Cells

TLDR

Human pluripotent stem cell–derived cardiomyocytes remain immature, limiting their use, and maturation normally involves a metabolic switch from glucose to fatty acids. The study tested whether supplementing fatty acids could promote maturation of hPSC‑CMs to improve their suitability for therapy, modeling, and drug screening. Fatty acid treatment induced hypertrophy, boosted force production, enhanced calcium transient peak and kinetics, increased action‑potential upstroke velocity and membrane capacitance, raised mitochondrial reserve capacity, upregulated fatty‑acid β‑oxidation genes, downregulated lipid‑synthesis genes, and activated multiple kinases, collectively advancing cardiomyocyte maturation.

Abstract

Although human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have emerged as a novel platform for heart regeneration, disease modeling, and drug screening, their immaturity significantly hinders their application. A hallmark of postnatal cardiomyocyte maturation is the metabolic substrate switch from glucose to fatty acids. We hypothesized that fatty acid supplementation would enhance hPSC-CM maturation. Fatty acid treatment induces cardiomyocyte hypertrophy and significantly increases cardiomyocyte force production. The improvement in force generation is accompanied by enhanced calcium transient peak height and kinetics, and by increased action potential upstroke velocity and membrane capacitance. Fatty acids also enhance mitochondrial respiratory reserve capacity. RNA sequencing showed that fatty acid treatment upregulates genes involved in fatty acid β-oxidation and downregulates genes in lipid synthesis. Signal pathway analyses reveal that fatty acid treatment results in phosphorylation and activation of multiple intracellular kinases. Thus, fatty acids increase human cardiomyocyte hypertrophy, force generation, calcium dynamics, action potential upstroke velocity, and oxidative capacity. This enhanced maturation should facilitate hPSC-CM usage for cell therapy, disease modeling, and drug/toxicity screens.