Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan.
Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Honjo 1-1-1, Kumamoto 860-8556, Japan.
Cell Metab. 2014 May 6;19(5):780-94. doi: 10.1016/j.cmet.2014.03.017. Epub 2014 Apr 17.
Mouse embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are in a high-flux metabolic state, with a high dependence on threonine catabolism. However, little is known regarding amino acid metabolism in human ESCs/iPSCs. We show that human ESCs/iPSCs require high amounts of methionine (Met) and express high levels of enzymes involved in Met metabolism. Met deprivation results in a rapid decrease in intracellular S-adenosylmethionine (SAM), triggering the activation of p53-p38 signaling, reducing NANOG expression, and poising human iPSC/ESCs for differentiation, follow by potentiated differentiation into all three germ layers. However, when exposed to prolonged Met deprivation, the cells undergo apoptosis. We also show that human ESCs/iPSCs have regulatory systems to maintain constant intracellular Met and SAM levels. Our findings show that SAM is a key regulator for maintaining undifferentiated pluripotent stem cells and regulating their differentiation.
小鼠胚胎干细胞（ESCs）和诱导多能干细胞（iPSCs）处于高代谢通量状态，对苏氨酸分解代谢有很高的依赖性。然而，关于人类 ESCs/iPSCs 中的氨基酸代谢知之甚少。我们发现人类 ESCs/iPSCs 需要大量蛋氨酸（Met），并表达高水平参与 Met 代谢的酶。Met 剥夺会导致细胞内 S-腺苷甲硫氨酸（SAM）迅速减少，触发 p53-p38 信号的激活，降低 NANOG 的表达，并使人类 iPSC/ESC 分化，随后增强向三个胚层的分化。然而，当暴露于长期 Met 剥夺时，细胞会发生凋亡。我们还表明，人类 ESCs/iPSCs 具有调节系统来维持恒定的细胞内 Met 和 SAM 水平。我们的研究结果表明，SAM 是维持未分化多能干细胞和调节其分化的关键调节剂。
