Cell Metabolism
Volume 19, Issue 5, 6 May 2014, Pages 780-794
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Article
Methionine Metabolism Regulates Maintenance and Differentiation of Human Pluripotent Stem Cells

https://doi.org/10.1016/j.cmet.2014.03.017Get rights and content
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Highlights

  • SAM is essential for the maintenance of pluripotent stem cells

  • Decrease in [SAM]i by methionine deprivation led to p53-p38 signaling activation

  • Short methionine deprivation poises human ESCs/iPSCs for differentiation

  • Prolonged methionine deprivation induces apoptosis of pluripotent stem cells

Summary

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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