Methionine Metabolism Regulates Maintenance and Differentiation of Human Pluripotent Stem Cells

Abstract

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.

Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination

“…However, TDH is inactive in hESCs owing to genetic mutations in human; thus, it is unclear how hESCs, particularly the fast growing naive hESCs, circumvent TDH deficiency. Nonetheless, methionine and arginine have been demonstrated to be essential for regulating hESC self-renewal, epigenetic landscape and gene expression, possibly in a PI3K/AKT/ mTOR-dependent manner (Shiraki et al, 2014;Carroll et al, 2016). Therefore, this signalling cascade also has crucial functions in maintaining PSC properties through the modulation of cellular metabolism.…”

“…Deficiency of autophagy in ESCs under such stress conditions leads to apoptosis or detrimental accumulation of pluripotency-associated proteins that compromise the pluripotent state (Mizushima et al, 2001;Cho et al, 2014). Expanding on the crucial role of mTORC1 in nutrient sensing, several amino acid pathways have been reported to be essential for the maintenance of PSC properties Carroll et al, 2016;Shiraki et al, 2014;Carey et al, 2015). Pluripotent mESCs are dependent on threonine catabolism by threonine dehydrogenase (TDH) for the synthesis of SAM, which in turn regulates histone methylations that drive ESC self-renewal and pluripotency ShyhChang et al, 2013).…”

Metabolic control of cancer cell stemness: Lessons from iPS cells

“…42 The high-flux metabolic state of iPS cells relies not only on a high dependence on threonine catabolism but also on large amounts of methionine; thus, iPS cells display regulatory systems to maintain a constant level of intracellular methionine and S-adenosylmethionine (SAM), a key regulator for maintaining undifferentiated iPS cells and regulating their differentiation. 86 Whether the acquisition of CSC cellular states and CSC self-renewal and differentiation similarly relies on TDH-related purine biosynthesis and/or methionine metabolism remains an unexplored area in the field of CSC biology. Nevertheless, the fact that threonine provides a substantial fraction of both cellular glycine and the acetyl-coenzyme A required for SAM synthesis, together with the recently recognized ability of SAM to influence trimethylation of histone H3 lysine 4 (H3K4me3), 87 provides a probable epigenetic mechanism by which modulation of a metabolic pathway might directly influence aberrant stemness in cancer tissues.…”

Essential roles of methionine and S -adenosylmethionine in the autarkic lifestyle of Mycobacterium tuberculosis

“…Methionine and S-adenosylmethionine (SAM) are essential metabolites that have gained considerable scientific attention because of their recently discovered roles as sentinel metabolites in the control of the eukaryotic cell cycle (10), autophagy (11), and differentiation of human pluripotent stem cells (12). Methionine takes a leading role in translation initiation (13) and is the precursor of SAM, a cofactor for one-carbon metabolism, the process responsible for the methylation of DNA, RNA, proteins, and lipids by SAM-dependent methyltransferases (14).…”