Department of Biochemistry and Molecular Biology, University of Georgia, 500 D.W. Brooks Drive, Athens, GA 30602, USA; Center for Molecular Medicine, University of Georgia, 500 D.W. Brooks Drive, Athens, GA 30602, USA.
Department of Biochemistry and Molecular Biology, University of Georgia, 500 D.W. Brooks Drive, Athens, GA 30602, USA; Complex Carbohydrate Research Center, University of Georgia, 315 Riverbend Road, Athens, GA 30602, USA.
Cell Stem Cell. 2017 Oct 5;21(4):502-516.e9. doi: 10.1016/j.stem.2017.08.018. Epub 2017 Sep 28.
As human pluripotent stem cells (hPSCs) exit pluripotency, they are thought to switch from a glycolytic mode of energy generation to one more dependent on oxidative phosphorylation. Here we show that, although metabolic switching occurs during early mesoderm and endoderm differentiation, high glycolytic flux is maintained and, in fact, essential during early ectoderm specification. The elevated glycolysis observed in hPSCs requires elevated MYC/MYCN activity. Metabolic switching during endodermal and mesodermal differentiation coincides with a reduction in MYC/MYCN and can be reversed by ectopically restoring MYC activity. During early ectodermal differentiation, sustained MYCN activity maintains the transcription of "switch" genes that are rate-limiting for metabolic activity and lineage commitment. Our work, therefore, shows that metabolic switching is lineage-specific and not a required step for exit of pluripotency in hPSCs and identifies MYC and MYCN as developmental regulators that couple metabolism to pluripotency and cell fate determination.
当人类多能干细胞（hPSCs）退出多能性时，人们认为它们会从糖酵解的能量生成模式转变为更依赖氧化磷酸化的模式。在这里，我们表明，尽管在早期中胚层和内胚层分化过程中发生了代谢转换，但高糖酵解通量仍然维持，并且在早期外胚层特化过程中实际上是必需的。在 hPSCs 中观察到的升高的糖酵解需要升高的 MYC/MYCN 活性。在内胚层和中胚层分化过程中的代谢转换与 MYC/MYCN 的减少同时发生，并且可以通过异位恢复 MYC 活性来逆转。在早期外胚层分化过程中，持续的 MYCN 活性维持“开关”基因的转录，这些基因是代谢活性和谱系决定的限速基因。因此，我们的工作表明，代谢转换是谱系特异性的，对于 hPSCs 退出多能性不是必需的步骤，并确定 MYC 和 MYCN 作为发育调节剂，将代谢与多能性和细胞命运决定联系起来。
