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

Abstract

SUMMARY The rate of glycolytic metabolism changes during differentiation of human embryonic stem cells (hESCs) and reprogramming of somatic cells to pluripotency. However, the functional contribution of glycolytic metabolism to the pluripotent state is unclear. Here we show that naive hESCs exhibit increased glycolytic flux, MYC transcriptional activity, and nuclear N-MYC localization relative to primed hESCs. This status is consistent with the inner cell mass of human blastocysts, where MYC transcriptional activity and nuclear N-MYC levels are also higher than in primed hESCs. Reduction of glycolysis decreases self-renewal of naive hESCs and feeder-free 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 human naive pluripotency and differences in the metabolism of feeder-/feeder-free cultured hESCs. They may also suggest methods for regulating self-renewal and initial cell fate specification of hESCs.

A Glycolytic Solution for Pluripotent Stem Cells

“…At the same time, human and mouse naïve PSCs exhibit increased OXPHOS (Takashima et al, 2014;Zhou et al, 2012). Now Gu et al (2016) demonstrate that human naïve PSCs, both newly derived and those cultured in previously reported reversion conditions (Takashima et al, 2014;Theunissen et al, 2014), in addition to higher mitochondrial oxygen consumption also display elevated glycolytic rates. Human naïve PSCs consumed more glucose, produced more lactate, and incorporated more glucose carbons into lactate and into purine and pyrimidine nucleotides, implying increased flux towards glycolysis and the PPP.…”

“…This is in contrast with the reduction of glycolytic metabolism previously found in mouse naïve PSCs (Zhou et al, 2012). Gu et al (2016) suggest that this discrepancy may be due to species-related differences. In particular, they observed that nuclear C-MYC, which promotes glucose metabolism, is higher in primed PSCs in mice, while it is higher in naïve PSCs in humans.…”

“…Two new papers in Cell Stem Cell and Cell Reports (Gu et al, 2016;Zhang et al, 2016) employ metabolic flux analysis to demonstrate that PSCs, even while maintaining pluripotency, dynamically modulate their glycolytic metabolism in response to changes in the culture conditions or conversion between different PSC states. Gu et al (2016) investigated the metabolic changes occurring during the transition between human naïve and primed pluripotent states. These two PSC states respectively represent pre-implantation cells in the inner cell mass and post-implantation cells in the epiblast (Takashima et al, 2014;Theunissen et al, 2014).…”

“…In particular, they observed that nuclear C-MYC, which promotes glucose metabolism, is higher in primed PSCs in mice, while it is higher in naïve PSCs in humans. Accordingly, using RNA-Seq analysis, Gu et al (2016) identified significant enrichment of MYC-regulated gene sets in human naïve versus primed PSCs.…”

“…The concomitant raise of OXPHOS and glycolysis observed by Gu et al (2016) might be a consequence of the bivalent metabolic state of naïve PSCs, which can switch to one or the other metabolic route according to the demand (Zhou et al, 2012). In fact, it has been suggested that glycolysis may represent the basal energy source for naïve PSCs and mitochondrial respiration their spare capacity (Carbognin et al, 2016).…”