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

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 ?-ketoglutarate (?KG) was shown to favor self-renewal in naive mouse embryonic stem cells (mESCs). The effect of ?KG or ?KG/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 ?KG or ?KG-to-succinate ratios accelerate, and elevated succinate levels delay, primed PSC differentiation. ?KG has been shown to inhibit the mitochondrial ATP synthase and to regulate epigenome-modifying dioxygenase enzymes. Mitochondrial uncoupling did not impede ?KG-accelerated primed PSC differentiation. Instead, ?KG induced, and succinate impaired, global histone and DNA demethylation in primed PSCs. The data support ?KG promotion of self-renewal or differentiation depending on the pluripotent state.

SUBMITTER: TeSlaa T 

PROVIDER: S-EPMC5023506 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature