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

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