TY - JOUR
T1 - Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells
AU - Takubo, Keiyo
AU - Nagamatsu, Go
AU - Kobayashi, Chiharu I.
AU - Nakamura-Ishizu, Ayako
AU - Kobayashi, Hiroshi
AU - Ikeda, Eiji
AU - Goda, Nobuhito
AU - Rahimi, Yasmeen
AU - Johnson, Randall S.
AU - Soga, Tomoyoshi
AU - Hirao, Atsushi
AU - Suematsu, Makoto
AU - Suda, Toshio
N1 - Funding Information:
We thank T. Kitamura for providing the Plat-E packaging cell line and pMY-IRES-EGFP vector, K. Rajewsky for providing Mx1-Cre mice, Primetech for OCR analysis by XF96, V. Haase for providing VHL flox/flox mice, R.A. Harris for providing Pdk2 −/− :Pdk4 −/− mice, and T. Muraki, K. Igarashi, K. Saito, and T. Hirose for technical support and laboratory management. K.T. is supported by the Global COE Programs for Human Metabolomic Systems Biology (for M.S.) and for Stem Cell Medicine and in part by a MEXT Grant-in-Aid for Young Scientists (A). A.H. and M.S. were supported in part by a MEXT Grant-in-Aid for Creative Scientific Research (17GS0419). FACS analysis was supported by M.S., the Leader of the JST, ERATO, and Suematsu Gas Biology Project. T.S. and K.T. were supported in part by a MEXT Grant-in-Aid for Scientific Research (A), a MEXT Grant-in-Aid for Scientific Research on Innovative Areas, and the Project for Realization of Regenerative Medicine from MEXT.
PY - 2013/1/3
Y1 - 2013/1/3
N2 - 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 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.
AB - 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 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.
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U2 - 10.1016/j.stem.2012.10.011
DO - 10.1016/j.stem.2012.10.011
M3 - Article
C2 - 23290136
AN - SCOPUS:84872011926
SN - 1934-5909
VL - 12
SP - 49
EP - 61
JO - Cell Stem Cell
JF - Cell Stem Cell
IS - 1
ER -