title: Glutamine Oxidation Is Indispensable for Survival of Human Pluripotent Stem Cells.
abstract: Human pluripotent stem cells (hPSCs) are uniquely dependent on aerobic glycolysis to generate ATP. However, the importance of oxidative phosphorylation (OXPHOS) has not been elucidated. Detailed amino acid profiling has revealed that glutamine is indispensable for the survival of hPSCs. Under glucose- and glutamine-depleted conditions, hPSCs quickly died due to the loss of ATP. Metabolome analyses showed that hPSCs oxidized pyruvate poorly and that glutamine was the main energy source for OXPHOS. hPSCs were unable to utilize pyruvate-derived citrate due to negligible expression of aconitase 2 (ACO2) and isocitrate dehydrogenase 2/3 (IDH2/3) and high expression of ATP-citrate lyase. Cardiomyocytes with mature mitochondria were not able to survive without glucose and glutamine, although they were able to use lactate to synthesize pyruvate and glutamate. This distinguishing feature of hPSC metabolism allows preparation of clinical-grade cell sources free of undifferentiated hPSCs, which prevents tumor formation during stem cell therapy.
authors.affiliation: Department of Cardiology, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan; Japan Society for the Promotion of Science, Tokyo 102-8472, Japan.
authors.forename: Shugo
authors.initials: S
authors.lastname: Tohyama
authors.affiliation: Department of Cardiology, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: jfujita@a6.keio.jp.
authors.forename: Jun
authors.initials: J
authors.lastname: Fujita
authors.affiliation: Department of Biochemistry, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan; Clinical and Translational Research Center, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Hishiki
authors.affiliation: Department of Biochemistry, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan; Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Suematsu Gas Biology Project, Tokyo 160-8582, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Matsuura
authors.affiliation: Department of Cardiology, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan; Asubio Pharma, Kobe 650-0047, Japan.
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Hattori
authors.affiliation: Department of Cardiology, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Rei
authors.initials: R
authors.lastname: Ohno
authors.affiliation: Department of Cardiology, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kanazawa
authors.affiliation: Department of Cardiology, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Seki
authors.affiliation: Department of Cardiology, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Nakajima
authors.affiliation: Department of Cardiology, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Kishino
authors.affiliation: Department of Cardiology, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Marina
authors.initials: M
authors.lastname: Okada
authors.affiliation: Department of Cardiovascular Surgery, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Hirano
authors.affiliation: Division of Cell-based Therapeutic Products, National Institute of Health Sciences, Tokyo 158-8501, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Kuroda
authors.affiliation: Division of Cell-based Therapeutic Products, National Institute of Health Sciences, Tokyo 158-8501, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yasuda
authors.affiliation: Division of Cell-based Therapeutic Products, National Institute of Health Sciences, Tokyo 158-8501, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Cardiology, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Yuasa
authors.affiliation: Department of Cardiology, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Motoaki
authors.initials: M
authors.lastname: Sano
authors.affiliation: Department of Biochemistry, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan; Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Suematsu Gas Biology Project, Tokyo 160-8582, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Suematsu
authors.affiliation: Department of Cardiology, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: kfukuda@a2.keio.jp.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D002952:Citric Acid Cycle; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D010084:Oxidation-Reduction; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism
chemical_list: D005973:Glutamine; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D005947:Glucose