Glycolytic Metabolism Plays a Functional Role in Regulating Human Pluripotent Stem Cell State

The rate of glycolytic metabolism changes during differentiation of human embryonic stem cells (hESCs) and reprogramming of somatic cells to pluripotent stem cells. However, the functional contribution of glycolytic metabolism to pluripotency is unclear. Here we show that the degree of pluripotency is associated with glycolytic rate, whereby naive hESCs exhibit increased glycolytic flux, MYC transcriptional activity, and nuclear localization of N-MYC relative to primed hESCs. This is consistent with the inner cell mass of human blastocysts which exhibit increased MYC transcriptional activity relative primed hESCs and elevated nuclear N-MYC levels. Reduction of glycolysis decreases self-renewal of naive hESCs and feeder-free cultured primed hESCs, but not primed hESCs grown in feeder-supported conditions. Reduction of glycolysis in feeder-free primed hESCs also enhances neural specification. These findings reveal associations between glycolytic metabolism and the state of pluripotency, differences in the metabolism of feeder- versus feeder-free cultured hESCs, and identify methods for regulating self-renewal and initial cell fate specification of hESCs