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Cell Metab. 2016 Sep 13;24(3):485-493. doi: 10.1016/j.cmet.2016.07.002. Epub 2016 Jul 28.

α-Ketoglutarate Accelerates the Initial Differentiation of Primed Human Pluripotent Stem Cells.

Author information

1
Molecular Biology Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA.
2
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
3
Department of Molecular Biology, Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
4
Department of Biology, California State University, Northridge, Northridge, CA 91330, USA.
5
Molecular Biology Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.
6
Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Metabolomics Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
7
Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Metabolomics Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.
8
Molecular Biology Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Bioengineering, Department of Pediatrics, and Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: mteitell@mednet.ucla.edu.

Abstract

Pluripotent stem cells (PSCs) can self-renew or differentiate from naive or more differentiated, primed, pluripotent states established by specific culture conditions. Increased intracellular α-ketoglutarate (αKG) was shown to favor self-renewal in naive mouse embryonic stem cells (mESCs). The effect of αKG or αKG/succinate levels on differentiation from primed human PSCs (hPSCs) or mouse epiblast stem cells (EpiSCs) remains unknown. We examined primed hPSCs and EpiSCs and show that increased αKG or αKG-to-succinate ratios accelerate, and elevated succinate levels delay, primed PSC differentiation. αKG has been shown to inhibit the mitochondrial ATP synthase and to regulate epigenome-modifying dioxygenase enzymes. Mitochondrial uncoupling did not impede αKG-accelerated primed PSC differentiation. Instead, αKG induced, and succinate impaired, global histone and DNA demethylation in primed PSCs. The data support αKG promotion of self-renewal or differentiation depending on the pluripotent state.

PMID:
27476976
PMCID:
PMC5023506
DOI:
10.1016/j.cmet.2016.07.002
[Indexed for MEDLINE]
Free PMC Article

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