Methionine Metabolism Regulates Maintenance and Differentiation of Human Pluripotent Stem Cells

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. [Display omitted] •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 Shiraki et al. show that human iPSC/ESCs rely on methionine metabolism to maintain pluripotency and self-renewal via the methionine intermediate SAM. Methionine deprivation reduces SAM levels, which primes iPSC/ESCs toward differentiation and ultimately triggers cell death. Differences in SAM dependence improve differentiation efficiency by selectively eliminating undifferentiated cells.