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Cell Metab. 2016 Apr 12;23(4):663-74. doi: 10.1016/j.cmet.2016.03.001. Epub 2016 Mar 31.

Glutamine Oxidation Is Indispensable for Survival of Human Pluripotent Stem Cells.

Author information

1
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.
2
Department of Cardiology, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: jfujita@a6.keio.jp.
3
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.
4
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.
5
Department of Cardiology, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan; Asubio Pharma, Kobe 650-0047, Japan.
6
Department of Cardiology, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan.
7
Department of Cardiovascular Surgery, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan.
8
Division of Cell-based Therapeutic Products, National Institute of Health Sciences, Tokyo 158-8501, Japan.
9
Department of Cardiology, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: kfukuda@a2.keio.jp.

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.

PMID:
27050306
DOI:
10.1016/j.cmet.2016.03.001
[Indexed for MEDLINE]
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