title: 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.
authors.affiliation: Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Shiraki
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Honjo 1-1-1, Kumamoto 860-8556, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Shiraki
authors.affiliation: Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan; Program for Leading Graduate Schools "HIGO," Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Tsuyama
authors.affiliation: Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan; CREST, Japan Science and Technology Agency, Chiyoda-ku, Tokyo 102-0075, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Obata
authors.affiliation: Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan; CREST, Japan Science and Technology Agency, Chiyoda-ku, Tokyo 102-0075, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Miura
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Komaba 4-6-1, Meguro-ku, Tokyo 153-8904, Japan.
authors.forename: Genta
authors.initials: G
authors.lastname: Nagae
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Komaba 4-6-1, Meguro-ku, Tokyo 153-8904, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.affiliation: Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan; Department of Neuropharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Kume
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Honjo 1-1-1, Kumamoto 860-8556, Japan. Electronic address: fendo@kumamoto-u.ac.jp.
authors.forename: Fumio
authors.initials: F
authors.lastname: Endo
authors.affiliation: Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan; Program for Leading Graduate Schools "HIGO," Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan. Electronic address: skume@kumamoto-u.ac.jp.
authors.forename: Shoen
authors.initials: S
authors.lastname: Kume
mesh_terms: D017209:Apoptosis / Q000502:physiology; D059447:Cell Cycle Checkpoints / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D008715:Methionine / Q000378:metabolism*; D000071317:Nanog Homeobox Protein; D012436:S-Adenosylmethionine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D016159:Tumor Suppressor Protein p53; D012436:S-Adenosylmethionine; D008715:Methionine; D048051:p38 Mitogen-Activated Protein Kinases