Methionine metabolism regulates maintenance and differentiation of human pluripotent stem cells

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / physiology
  • Cell Cycle Checkpoints / physiology
  • Cell Differentiation / physiology*
  • Cells, Cultured
  • Embryonic Stem Cells / metabolism
  • Homeodomain Proteins / metabolism
  • Humans
  • Induced Pluripotent Stem Cells / metabolism*
  • Methionine / metabolism*
  • Nanog Homeobox Protein
  • S-Adenosylmethionine / metabolism
  • Signal Transduction / physiology
  • Tumor Suppressor Protein p53 / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Homeodomain Proteins
  • NANOG protein, human
  • Nanog Homeobox Protein
  • Tumor Suppressor Protein p53
  • S-Adenosylmethionine
  • Methionine
  • p38 Mitogen-Activated Protein Kinases