Zhang Hui, Badur Mehmet G, Divakaruni Ajit S, Parker Seth J, Jäger Christian, Hiller Karsten, Murphy Anne N, Metallo Christian M
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92037, USA.
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92037, USA.
Cell Rep. 2016 Aug 9;16(6):1536-1547. doi: 10.1016/j.celrep.2016.06.102. Epub 2016 Jul 28.
Recent studies have suggested that human pluripotent stem cells (hPSCs) depend primarily on glycolysis and only increase oxidative metabolism during differentiation. Here, we demonstrate that both glycolytic and oxidative metabolism can support hPSC growth and that the metabolic phenotype of hPSCs is largely driven by nutrient availability. We comprehensively characterized hPSC metabolism by using (13)C/(2)H stable isotope tracing and flux analysis to define the metabolic pathways supporting hPSC bioenergetics and biosynthesis. Although glycolytic flux consistently supported hPSC growth, chemically defined media strongly influenced the state of mitochondrial respiration and fatty acid metabolism. Lipid deficiency dramatically reprogramed pathways associated with fatty acid biosynthesis and NADPH regeneration, altering the mitochondrial function of cells and driving flux through the oxidative pentose phosphate pathway. Lipid supplementation mitigates this metabolic reprogramming and increases oxidative metabolism. These results demonstrate that self-renewing hPSCs can present distinct metabolic states and highlight the importance of medium nutrients on mitochondrial function and development.
近期研究表明，人类多能干细胞（hPSC）主要依赖糖酵解，仅在分化过程中增加氧化代谢。在此，我们证明糖酵解和氧化代谢均可支持hPSC的生长，且hPSC的代谢表型在很大程度上受营养物质可用性的驱动。我们通过使用¹³C/²H稳定同位素示踪和通量分析来全面表征hPSC的代谢，以确定支持hPSC生物能量学和生物合成的代谢途径。尽管糖酵解通量始终支持hPSC的生长，但化学成分明确的培养基强烈影响线粒体呼吸和脂肪酸代谢的状态。脂质缺乏显著重新编程了与脂肪酸生物合成和NADPH再生相关的途径，改变了细胞的线粒体功能并驱动通过氧化戊糖磷酸途径的通量。补充脂质可减轻这种代谢重编程并增加氧化代谢。这些结果表明，自我更新的hPSC可呈现不同的代谢状态，并突出了培养基营养物质对线粒体功能和发育的重要性。
