Journal
CELL STEM CELL
Volume 12, Issue 1, Pages 49-61Publisher
CELL PRESS
DOI: 10.1016/j.stem.2012.10.011
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Funding
- Global COE Program for Human Metabolomic Systems Biology
- Global COE Program for Stem Cell Medicine
- MEXT [17GS0419]
- Grants-in-Aid for Scientific Research [22130001, 22134007, 23689049, 17GS0419, 23590370] Funding Source: KAKEN
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Defining the metabolic programs that underlie stem cell maintenance will be essential for developing strategies to manipulate stem cell capacity. Mammalian hematopoietic stem cells (HSCs) maintain cell cycle quiescence in a hypoxic microenvironrnent. It has been proposed that HSCs exhibit a distinct metabolic phenotype under these conditions. Here we directly investigated this idea using metabolomic analysis and found that HSCs generate adenosine-5'-triphosphate by anaerobic glycolysis through a pyruvate dehydrogenase kinase (Pdk)-dependent mechanism. Elevated Pdk expression leads to active suppression of the influx of glycolytic metabolites into mitochondria. Pdk overexpression in glycolysis-defective HSCs restored glycolysis, cell cycle quiescence, and stem cell capacity, while loss of both Pdk2 and Pdk4 attenuated HSC quiescence, glycolysis, and transplantation capacity. Moreover, treatment of HSCs with a Pdk mimetic promoted their survival and transplantation capacity. Thus, glycolytic metabolic status governed by Pdk acts as a cell cycle checkpoint that modulates HSC quiescence and function.
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