School of BioSciences, The University of Melbourne, Parkville, Victoria, Australia.
O'Brien Institute Department, St Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.
Stem Cells. 2020 May;38(5):624-638. doi: 10.1002/stem.3152. Epub 2020 Feb 4.
Nicotinamide adenine dinucleotide (NAD ) and its precursor metabolites are emerging as important regulators of both cell metabolism and cell state. Interestingly, the role of NAD in human embryonic stem cell (hESC) metabolism and the regulation of pluripotent cell state is unresolved. Here we show that NAD simultaneously increases hESC mitochondrial oxidative metabolism and partially suppresses glycolysis and stimulates amino acid turnover, doubling the consumption of glutamine. Concurrent with this metabolic remodeling, NAD increases hESC pluripotent marker expression and proliferation, inhibits BMP4-induced differentiation and reduces global histone 3 lysine 27 trimethylation, plausibly inducing an intermediate naïve-to-primed bivalent metabolism and pluripotent state. Furthermore, maintenance of NAD recycling via malate aspartate shuttle activity is identified as an absolute requirement for hESC self-renewal, responsible for 80% of the oxidative capacity of hESC mitochondria. Our findings implicate NAD in the regulation of cell state, suggesting that the hESC pluripotent state is dependent upon cellular NAD .
烟酰胺腺嘌呤二核苷酸（NAD）及其前体代谢物正在成为细胞代谢和细胞状态的重要调节因子。有趣的是，NAD 在人胚胎干细胞（hESC）代谢和多能性细胞状态调控中的作用尚未得到解决。在这里，我们发现 NAD 同时增加 hESC 线粒体氧化代谢，部分抑制糖酵解并刺激氨基酸周转，使谷氨酰胺的消耗增加一倍。伴随着这种代谢重塑，NAD 增加 hESC 多能性标志物的表达和增殖，抑制 BMP4 诱导的分化，并降低组蛋白 3 赖氨酸 27 三甲基化的全局水平，可能诱导中间的原始到启动的二价代谢和多能状态。此外，通过苹果酸天冬氨酸穿梭活性维持 NAD 循环被鉴定为 hESC 自我更新的绝对要求，负责 hESC 线粒体氧化能力的 80%。我们的研究结果表明 NAD 参与了细胞状态的调控，提示 hESC 多能状态依赖于细胞 NAD。
