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Defining the mechanisms and consequences of glycolytic metabolism in human pluripotent stem cells

ABSTRACT: The balance between glycolytic and oxidative metabolism shifts during differentiation of human embryonic stem cells (hESCs) and during reprogramming of somatic cells into pluripotent stem cells. However the contribution of glycolytic metabolism to various stages of pluripotency is not well understood. Additionally, few tools have been developed that modulate pluripotent stem cell glycolytic metabolism to influence self-renewal or differentiation. Here we show that the degree of human pluripotency is associated with glycolytic rate, whereby naive hESCs exhibit higher glycolytic flux, increased MYC transcriptional activity, and elevated nuclear N-MYC levels relative to primed hESCs. Consistently, the inner cell mass of human blastocysts also exhibits increased MYC transcriptional activity relative to primed hESCs and elevated nuclear N-MYC levels. Expression of the lactate transporter, monocarboxylate transporter 1 (MCT1), is strongly associated with the pluripotent state, and reduction of glycolysis using a small molecule inhibitor towards MCT1 decreases self-renewal of naïve hESCs and feeder-free cultured primed hESCs, but not that of primed hESCs grown in feeder-supported conditions. Lastly, reduction of glycolytic metabolism via MCT1 inhibition in feeder-free primed hESCs enhances neural lineage specification. These findings validate the association between glycolytic metabolism and pluripotency, reveal differences in the glucose metabolism of feeder- versus feeder-free cultured hESCs, and show that pharmacologic regulation of glycolysis can influence self-renewal and initial cell fate specification of human pluripotent stem cells. Overall design: We hypothesized that human pluripotent stem cells, cultured with or without feeder cells (Mouse Embryonic Fibroblasts, or MEFs), might display different metabolic phenotyes, and secreted factors by MEFs might be responsible for reprogramming the metabolism of human pluripotent stem cells. To test these hypotheses, we generated whole genome microarray data from human embryonic stem cell lines, with or without feeders, and feeder-free hESCs treated for 24 hours with MEF-conditioned or unconditioned medium. In addition, to understand how glycolysis inhibition changes the gene expression of human pluripotent cells, our study also included human embryonic stem cells treated for five days with DMSO or 250 nM AZD3965, a small molecule inhibitor towards monocarboxylate transport 1, or MCT1.

INSTRUMENT(S): [HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array

SUBMITTER: Heather Christofk  

PROVIDER: GSE83491 | GEO | 2016-08-16



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

Gu Wen W   Gaeta Xavier X   Sahakyan Anna A   Chan Alanna B AB   Hong Candice S CS   Kim Rachel R   Braas Daniel D   Plath Kathrin K   Lowry William E WE   Christofk Heather R HR  

Cell stem cell 20160908 4

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 transcripti  ...[more]

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