Methionine Metabolism Regulates Maintenance and Differentiation of Human Pluripotent Stem Cells
2014; Cell Press; Volume: 19; Issue: 5 Linguagem: Inglês
10.1016/j.cmet.2014.03.017
ISSN1932-7420
AutoresNobuaki Shiraki, Yasuko Shiraki, Tomonori Tsuyama, Fumiaki Obata, Masayuki Miura, Genta Nagae, Hiroyuki Aburatani, Kazuhiko Kume, Fumio Endo, Shoen Kume,
Tópico(s)Renal and related cancers
ResumoMouse 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.
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