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

Tara TeSlaa; Andrea C Chaikovsky; Inna Lipchina; Sandra L Escobar; Konrad Hochedlinger; Jing Huang; Thomas G Graeber; Daniel Braas; Michael A Teitell

doi:10.1016/j.cmet.2016.07.002

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

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

Authors

Tara TeSlaa¹, Andrea C Chaikovsky², Inna Lipchina³, Sandra L Escobar⁴, Konrad Hochedlinger³, Jing Huang⁵, Thomas G Graeber⁶, Daniel Braas⁷, Michael A Teitell⁸

Affiliations

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.

MeSH terms

Cell Differentiation / drug effects*
Cell Lineage / drug effects
Citric Acid Cycle / drug effects
DNA Methylation / drug effects
Epigenomics
Histones / metabolism
Humans
Ketoglutaric Acids / pharmacology*
Metabolome / drug effects
Pluripotent Stem Cells / cytology*
Pluripotent Stem Cells / drug effects
Pluripotent Stem Cells / metabolism
Succinic Acid / metabolism
Transaminases / metabolism

Substances

Histones
Ketoglutaric Acids
Succinic Acid
Transaminases

Abstract

MeSH terms

Substances

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