Methionine metabolism regulates maintenance and differentiation of human pluripotent stem cells

Nobuaki Shiraki; Yasuko Shiraki; Tomonori Tsuyama; Fumiaki Obata; Masayuki Miura; Genta Nagae; Hiroyuki Aburatani; Kazuhiko Kume; Fumio Endo; Shoen Kume

doi:10.1016/j.cmet.2014.03.017

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.

Authors

Affiliations

¹ Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan.
² Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Honjo 1-1-1, Kumamoto 860-8556, Japan.
³ 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.
⁴ 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.
⁵ Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Komaba 4-6-1, Meguro-ku, Tokyo 153-8904, Japan.
⁶ 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.
⁷ 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.
⁸ 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.

PMID: 24746804
DOI: 10.1016/j.cmet.2014.03.017

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.

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

Substances

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