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

Wen Gu; Xavier Gaeta; Anna Sahakyan; Alanna B Chan; Candice S Hong; Rachel Kim; Daniel Braas; Kathrin Plath; William E Lowry; Heather R Christofk

doi:10.1016/j.stem.2016.08.008

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

Cell Stem Cell. 2016 Oct 6;19(4):476-490. doi: 10.1016/j.stem.2016.08.008. Epub 2016 Sep 8.

Authors

Affiliations

¹ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Metabolomics Center, Los Angeles, CA 90095, USA.
⁶ Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
⁷ Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. Electronic address: blowry@ucla.edu.
⁸ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; UCLA Metabolomics Center, Los Angeles, CA 90095, USA. Electronic address: hchristofk@mednet.ucla.edu.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

Monocarboxylic Acid Transporters
N-Myc Proto-Oncogene Protein
Symporters
monocarboxylate transport protein 1
Glucose

Abstract

Publication types

MeSH terms

Substances

Grants and funding