Distinct carbon sources affect structural and functional maturation of cardiomyocytes derived from human pluripotent stem cells.
Distinct carbon sources affect structural and functional maturation of cardiomyocytes derived from human pluripotent stem cells.
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DOI：
10.1038/s41598-017-08713-4
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发表时间：
2017-08-17
影响因子：
4.6
通讯作者：
Alves PM
中科院分区：
文献类型：
--
作者：
Correia C;Koshkin A;Duarte P;Hu D;Teixeira A;Domian I;Serra M;Alves PM
人多能干细胞衍生的心肌细胞（hPSC-CM）的不成熟表型限制了其在细胞治疗和药物测试中的潜力。在这项研究中，我们报告了将hPSC-CM从含葡萄糖的培养基转移到含半乳糖和脂肪酸的培养基促进其快速成熟为成人样CM，具有更高的氧化代谢，更接近成人心室组织的转录特征，更高的肌原纤维密度和排列，改善的钙处理，增强的收缩性和更多的生理动作电位动力学。综合“组学”分析表明，向培养基中添加半乳糖提高了细胞的总氧化能力，并改善了脂肪酸氧化，避免了细胞暴露于高脂肪酸水平导致的脂毒性。本研究提供了hPSC-CM的底物利用和功能成熟之间的重要联系，促进了这种有前途的细胞类型在临床和临床前应用中的应用。
The immature phenotype of human pluripotent stem cell derived cardiomyocytes (hPSC-CMs) constrains their potential in cell therapy and drug testing. In this study, we report that shifting hPSC-CMs from glucose-containing to galactose- and fatty acid-containing medium promotes their fast maturation into adult-like CMs with higher oxidative metabolism, transcriptional signatures closer to those of adult ventricular tissue, higher myofibril density and alignment, improved calcium handling, enhanced contractility, and more physiological action potential kinetics. Integrated “-Omics” analyses showed that addition of galactose to culture medium improves total oxidative capacity of the cells and ameliorates fatty acid oxidation avoiding the lipotoxicity that results from cell exposure to high fatty acid levels. This study provides an important link between substrate utilization and functional maturation of hPSC-CMs facilitating the application of this promising cell type in clinical and preclinical applications.