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Stem cells

A metabolic switch

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Mammalian haematopoietic stem cells are maintained in a resting quiescent state in specialized hypoxic niches in the bone marrow. In response to changes in the microenvironment, they can exit this state and rapidly proliferate and differentiate into different blood cell types. Complementary studies now reveal two important features of haematopoietic stem cell metabolism. Takubo et al. show that resting cells use anaerobic glycolysis as a source of energy and that this metabolic programme is required to maintain a functional quiescent state. Yu et al. find that a switch to mitochondrial respiration is needed for cells to differentiate.

quiescent haematopoietic stem cells rely on glycolysis for energy production

Takubo et al. analysed the metabolome of haematopoietic stem cells and their progeny. They found that stem cells, unlike their progeny, accumulated high levels of fructose-1,6-bisphosphate, which is indicative of active glycolysis. Next, the authors showed that glycolysis was decreased in haematopoietic stem cells lacking hypoxia-inducible factor 1α (HIF1α; which is a transcription factor essential for haematopoietic function and for the maintenance of quiescence), whereas mitochondrial metabolism was activated in these cells. HIF1α was shown to promote the expression of pyruvate dehydrogenase kinase 2 (PDK2) and PDK4, which prevent pyruvate from entering the tricarboxylic acid (TCA) cycle and thus prevent mitochondrial respiration. Furthermore, bone marrow from mice lacking both PDK2 and PDK4 had reduced transplantation capacity due to reduced cell quiescence and survival. This indicates that HIF1α-driven glycolysis is necessary for the maintenance of a functional quiescent haematopoietic stem cell population.

Yu et al. found that conditional knockout of Ptpmt1, which encodes a PTEN-like mitochondrial phosphatase required for mitochondrial respiration, resulted in haematopoietic failure in mice. Importantly, the population of haematopoietic stem cells drastically increased, but cells failed to differentiate. The mitochondrial bioenergetics regulated by PTPMT1 seems to be selectively important for differentiation of stem cells but not for self-renewal-associated cell division. Interestingly, the authors found that the requirement of PTPMT1 for differentiation was specific for stem cells and not for lineage-specific progenitor cells.

These studies show that quiescent haematopoietic stem cells rely on glycolysis for energy production but must switch to the more efficient ATP-producing mitochondrial respiration to enter a cell division programme associated with differentiation. As respiration is associated with the production of reactive oxygen species that could cause DNA damage, the alternative metabolic programme 'chosen' by resting cells protects them from accumulating damage that could impair their function in the maintenance of tissue homeostasis. Further studies should elucidate how the switch between these metabolic programmes is regulated, whether other metabolic pathways distinguish quiescent cells from their active progeny and whether similar metabolic programmes control the behaviour of other stem cell types.

ORIGINAL RESEARCH PAPERS

  1. Takubo, K. et al. Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. Cell Stem Cell 12, 49–61 (2013)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Yu, W.-M. et al. Metabolic regulation by the mitochondrial phosphatase PTPMT1 is required for hematopoietic stem cell differentiation. Cell Stem Cell 12, 62–74 (2013)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Baumann, K. A metabolic switch. Nat Rev Mol Cell Biol 14, 65 (2013). https://doi.org/10.1038/nrm3515

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  • DOI: https://doi.org/10.1038/nrm3515

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