Takubo, KeiyoNagamatsu, GoKobayashi, Chiharu I.Nakamura-Ishizu, AyakoKobayashi, HiroshiIkeda, EijiGoda, NobuhitoRahimi, YasmeenJohnson, Randall S.Soga, TomoyoshiHirao, AtsushiSuematsu, MakotoSuda, Toshio2019-08-262019-08-262013-01-03Takubo, K., Nagamatsu, G., Kobayashi, C. I., Nakamura-Ishizu, A., Kobayashi, H., Ikeda, E., … Suda, T. (2013). Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. Cell stem cell, 12(1), 49–61. doi:10.1016/j.stem.2012.10.011https://hdl.handle.net/1805/20578Defining 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 microenvironment. 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.en-USPublisher PolicyCell cycleGlycolysisHematopoietic stem cellsImmunohistochemistryProtein-Serine-Threonine KinasesArticle