Mathieu Julie, Zhou Wenyu, Xing Yalan, Sperber Henrik, Ferreccio Amy, Agoston Zsuzsa, Kuppusamy Kavitha T, Moon Randall T, Ruohola-Baker Hannele
Department of Biochemistry, University of Washington School of Medicine, Seattle, WA 98109-4714, USA; The Institute for Stem Cell and Regenerative Medicine (ISCRM), University of Washington School of Medicine, Seattle, WA 98109-4714, USA.
Department of Biology, University of Washington, Seattle, WA 98109-4714, USA; The Institute for Stem Cell and Regenerative Medicine (ISCRM), University of Washington School of Medicine, Seattle, WA 98109-4714, USA.
Cell Stem Cell. 2014 May 1;14(5):592-605. doi: 10.1016/j.stem.2014.02.012. Epub 2014 Mar 20.
Pluripotent stem cells have distinct metabolic requirements, and reprogramming cells to pluripotency requires a shift from oxidative to glycolytic metabolism. Here, we show that this shift occurs early during reprogramming of human cells and requires hypoxia-inducible factors (HIFs) in a stage-specific manner. HIF1α and HIF2α are both necessary to initiate this metabolic switch and for the acquisition of pluripotency, and the stabilization of either protein during early phases of reprogramming is sufficient to induce the switch to glycolytic metabolism. In contrast, stabilization of HIF2α during later stages represses reprogramming, partly because of the upregulation of TNF-related apoptosis-inducing ligand (TRAIL). TRAIL inhibits induced pluripotent stem cell (iPSC) generation by repressing apoptotic caspase 3 activity specifically in cells undergoing reprogramming but not human embryonic stem cells (hESCs), and inhibiting TRAIL activity enhances human iPSC generation. These results shed light on the mechanisms underlying the metabolic shifts associated with the acquisition of a pluripotent identity during reprogramming.
多能干细胞有独特的代谢需求，将细胞重编程为多能性需要从氧化代谢转变为糖酵解代谢。在此，我们表明这种转变发生在人类细胞重编程的早期，并且以阶段特异性的方式需要缺氧诱导因子（HIFs）。HIF1α和HIF2α对于启动这种代谢转换和获得多能性都是必需的，并且在重编程早期阶段任何一种蛋白的稳定都足以诱导向糖酵解代谢的转换。相比之下，在后期阶段HIF2α的稳定会抑制重编程，部分原因是肿瘤坏死因子相关凋亡诱导配体（TRAIL）的上调。TRAIL通过特异性抑制正在进行重编程的细胞而非人类胚胎干细胞（hESCs）中的凋亡半胱天冬酶3活性来抑制诱导多能干细胞（iPSC）的产生，并且抑制TRAIL活性可增强人类iPSC的产生。这些结果揭示了重编程过程中与获得多能性身份相关的代谢转变的潜在机制。
