Journal
CELL METABOLISM
Volume 19, Issue 5, Pages 780-794Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2014.03.017
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Funding
- National Institute of Biomedical Innovation
- NEXT Program by the Japanese Society for the Promotion of Science (JSPS)
- Project for Realization of Regenerative Medicine from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) Japan
- Program for Leading Graduate Schools HIGO (Health life science
- Interdisciplinary and Glocal Oriented) Program from MEXT
- Grants-in-Aid for Scientific Research [26461638, 26670384, 26253059] Funding Source: KAKEN
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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.
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