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

• Published in: Cell stem cell Vol. 19; no. 4; pp. 476 - 490
• Main Authors: Gu, Wen, Gaeta, Xavier, Sahakyan, Anna, Chan, Alanna B., Hong, Candice S., Kim, Rachel, Braas, Daniel, Plath, Kathrin, Lowry, William E., Christofk, Heather R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.10.2016
• Subjects: Animals; Cell Lineage - drug effects; Cell Proliferation - drug effects; Cells, Cultured; Embryo, Mammalian - cytology; Feeder Cells - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Glucose - metabolism; Glucose - pharmacology; Glycolysis - drug effects; Human Embryonic Stem Cells - cytology; Human Embryonic Stem Cells - drug effects; Human Embryonic Stem Cells - metabolism; Humans; Mice; Monocarboxylic Acid Transporters - antagonists & inhibitors; Monocarboxylic Acid Transporters - metabolism; N-Myc Proto-Oncogene Protein - metabolism; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - drug effects; Pluripotent Stem Cells - metabolism; Symporters - antagonists & inhibitors; Symporters - metabolism
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2016.08.008

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 is higher than in primed hESCs and nuclear N-MYC levels are elevated. 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. [Display omitted] •Naive hESCs show increased glycolysis compared to primed counterparts•High nuclear N-MYC is associated with human naive pluripotency•MEF-secreted factors make primed hESCs less reliant on glucose for proliferation•Reduction of glycolysis in feeder-free primed hESCs enhances neural specification Gu et al. examine the associations between glycolytic metabolism and the pluripotency state of hESCs under different naive and primed growth conditions. They identify differences in the metabolic state and highlight potential metabolic approaches for regulating self-renewal and initial cell fate specification of hESCs.