Mitochondrial and glycolytic remodeling during nascent neural differentiation of human pluripotent stem cells
Mitochondrial and glycolytic remodeling during nascent neural differentiation of human pluripotent stem cells
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DOI：
10.1242/dev.168997
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发表时间：
2018-10-01
期刊：
影响因子：
4.6
通讯作者：
Harvey, Alexandra J.
中科院分区：
文献类型：
--
作者：
Lees, Jarmon G.;Gardner, David K.;Harvey, Alexandra J.
据报道，随着人类多能干细胞（hPSC）退出多能性，它们从糖酵解能量产生转变为主要的线粒体代谢。在这里，我们表明，在外胚层分化为神经前体细胞（NPC），hPSC增加糖酵解速率，最终产生更多的碳作为乳酸比消耗的葡萄糖。然而，葡萄糖、乳酸盐和丙酮酸盐的利用率在NPC阶段降低至其PSC水平的一半，从而建立更静止的代谢状态。此外，我们表征了在分化的前24小时内的代谢退出事件，这对于将hPSC从多能状态转变出来是必要的。与目前的想法相反，线粒体质量在NPC诱导过程中不会增加。相反，线粒体DNA拷贝和线粒体活性降低，表明线粒体代谢需要抑制，或不需要，新生外胚层分化。因此，我们的工作与hPSC状态主要是糖酵解的教条形成对比，在失去多能状态时过渡到氧化代谢。相反，我们表明获得了提高的糖酵解代谢，表明糖酵解和线粒体代谢的代谢调节发生在hPSC退出多能性期间。
As human pluripotent stem cells (hPSCs) exit pluripotency, they reportedly switch from glycolytic energy production to primarily mitochondrial metabolism. Here, we show that upon ectoderm differentiation to neural precursor cells (NPCs), hPSCs increase glycolytic rate, ultimately producing more carbon as lactate than is consumed as glucose. However, glucose, lactate and pyruvate utilization decrease to half their PSC levels by the NPC stage, establishing a more quiescent metabolic state. Furthermore, we characterize a metabolic exit event within the first 24 h of differentiation, plausibly necessary to transition hPSCs out of the pluripotent state. Contrary to current thinking, mitochondrial mass does not increase during NPC induction. Instead, mitochondrial DNA copies and mitochondrial activity decrease, suggesting that mitochondrial metabolism either requires suppression, or is not required, for nascent ectoderm differentiation. Our work, therefore, contrasts with the dogma that the hPSC state is primarily glycolytic, transitioning to an oxidative metabolism upon the loss of the pluripotent state. Instead, we show that heightened glycolytic metabolism is acquired, indicating that metabolic modulation of both glycolysis and mitochondrial metabolism occurs during exit from pluripotency in hPSCs.