α-Ketoglutarate Accelerates the Initial Differentiation of Primed Human Pluripotent Stem Cells
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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.
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At later stages of pluripotency, α-KG derived from glutamine can promote early differentiation, suggesting that the stage of cellular maturity can alter the effect of α-KG.
“In addition, at later stages of pluripotency, α-KG derived from glutamine can promote early differentiation, suggesting that the stage of cellular maturity can alter the effect of α-KG105.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [105]
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Self-citation
- Authors
- TeSlaa, T., Chaikovsky, A. C., Lipchina, I., Escobar, S. L., Hochedlinger, K., Huang, J., Graeber, T. G., Braas, D., & Teitell, M. A.
- Affiliations
- University of California, Los Angeles (US)
- Harvard University (US)
- California State University, Northridge (US)
- California NanoSystems Institute (US)
- Corresponding author
- Teitell, Michael A.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-09
- Volume
- 24
- Issue
- 3
- Pages
- 485-493
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5023506
- OpenAlex
- W2504379340
- Cited by
- 287
- References
- 35
- Citations by year
- 2026: 32 · 2025: 28 · 2024: 20 · 2023: 23 · 2022: 37 · 2021: 27 · 2020: 38 · 2019: 30 · 2018: 20 · 2017: 28 · 2016: 4
- FWCI
- 14.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Cancer Institute (R01CA185189, R01CA090571, R01CA156674, P30CA016042)
- National Institute of General Medical Sciences (P01GM081621, R01GM073981, R01GM114188, T32GM007185)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- alpha-ketoglutarate, succinic acid, human pluripotent stem cells, epiblast stem cells, stem cell differentiation, self-renewal, histone demethylation, DNA demethylation, epigenetic regulation, mitochondrial uncoupling, mitochondrial ATP synthase, TCA cycle metabolism
- MeSH terms
- Transaminases, Cell Differentiation, Citric Acid Cycle, Histones, Humans, Ketoglutaric Acids, Cell Lineage, DNA Methylation, Succinic Acid, Pluripotent Stem Cells, Metabolome, Epigenomics
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