Distinct Metabolic States Can Support Self-Renewal and Lipogenesis in Human Pluripotent Stem Cells under Different Culture Conditions.
Distinct Metabolic States Can Support Self-Renewal and Lipogenesis in Human Pluripotent Stem Cells under Different Culture Conditions.
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DOI：
10.1016/j.celrep.2016.06.102
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发表时间：
2016-08-09
期刊：
影响因子：
8.8
通讯作者：
Metallo CM
中科院分区：
文献类型：
--
作者：
Zhang H;Badur MG;Divakaruni AS;Parker SJ;Jäger C;Hiller K;Murphy AN;Metallo CM
最近的研究表明，人类多能干细胞（hPSC）主要依赖于糖酵解，在分化过程中只增加氧化代谢。在这里，我们证明了糖酵解和氧化代谢都可以支持hPSC生长，并且hPSC的代谢表型在很大程度上由营养物质的可用性驱动。我们使用13 C/2 H稳定同位素示踪和通量分析来全面表征hPSC代谢，以定义支持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生长，但化学成分确定的培养基强烈影响线粒体呼吸和脂肪酸代谢的状态。脂质缺乏显著地重新编程与脂肪酸生物合成和NADPH再生相关的途径，改变细胞的线粒体功能并通过氧化戊糖磷酸途径驱动通量。脂质补充剂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可以呈现不同的代谢状态，并突出了培养基营养素对线粒体功能和发育的重要性。Zhang等人应用代谢通量分析来全面表征在不同培养基中培养的人多能干细胞的代谢。维持在化学成分确定的培养基中的细胞显著上调脂质生物合成和氧化还原途径以补偿培养基脂质缺乏，同时下调氧化线粒体代谢。
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 the metabolic phenotype of hPSCs is largely driven by nutrient availability. We comprehensively characterized hPSC metabolism using 13C/2H stable isotope tracing and flux analysis to define the metabolic pathways supporting hPSC bioenergetics and biosynthesis. Whereas glycolytic flux consistently supported hPSC growth, chemically-defined media strongly influenced that 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 reprograming 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. Zhang et al. applies metabolic flux analysis to comprehensively characterize the metabolism of human pluripotent stem cells cultured in different media. Cells maintained in chemically defined media significantly upregulate lipid biosynthesis and redox pathways to compensate for medium lipid deficiency while downregulating oxidative mitochondrial metabolism.