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

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...

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Bibliographic Details
Published in:	Stem cell reports 2019-10, Vol.13 (4), p.657-668
Main Authors:	Yang, Xiulan, Rodriguez, Marita L., Leonard, Andrea, Sun, Lihua, Fischer, Karin A., Wang, Yuliang, Ritterhoff, Julia, Zhao, Limei, Kolwicz, Stephen C., Pabon, Lil, Reinecke, Hans, Sniadecki, Nathan J., Tian, Rong, Ruohola-Baker, Hannele, Xu, Haodong, Murry, Charles E.
Format:	Article
Language:	eng
Subjects:	cardiomyocyte maturation embryonic stem cells fatty acids induced pluripotent stem cells metabolism
Online Access:	Get full text
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Summary:	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. •Fatty acid treatment leads to cardiomyocyte hypertrophy•Fatty acid treatment leads to enhanced contractile force generation•Fatty acid treatment leads to improved calcium transient kinetics•Fatty acid treatment leads to faster action potential maximum upstroke velocity In this article, Yang and colleagues show that fatty acid supplements enhance the maturation of cardiomyocytes derived from human pluripotent stem cells. Fatty acid treatment induces cardiomyocyte hypertrophy and significantly increases cardiomyocyte force production. The improvement in force generation is accompanied by enhanced calcium transient kinetics and faster action potential maximum upstroke velocity.
ISSN:	2213-6711 2213-6711