alpha-Ketoglutarate Accelerates the Initial Differentiation of Primed Human Pluripotent Stem Cells.
Induced stem cells can stay stem cells or differentiate into more mature cells and adult cells depending on the specific culture conditions. We have found that a specific gene, alphaketogluterate that is normally involved in cellular metabolism, is in charge of determining whether the cell stays a stem cell or differentiates into an adult cell.
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 (alphaKG) was shown to favor self-renewal in naive mouse embryonic stem cells (mESCs). The effect of alphaKG or alphaKG/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 alphaKG or alphaKG-to-succinate ratios accelerate, and elevated succinate levels delay, primed PSC differentiation. alphaKG has been shown to inhibit the mitochondrial ATP synthase and to regulate epigenome-modifying dioxygenase enzymes. Mitochondrial uncoupling did not impede alphaKG-accelerated primed PSC differentiation. Instead, alphaKG induced, and succinate impaired, global histone and DNA demethylation in primed PSCs. The data support alphaKG promotion of self-renewal or differentiation depending on the pluripotent state.