Editors' ChoiceStem Cells

Preventing Depletion

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Science Signaling  07 Dec 2010:
Vol. 3, Issue 151, pp. ec370
DOI: 10.1126/scisignal.3151ec370

Blood cells are continuously produced throughout life from hematopoietic stem cells (HSCs), which can transition between a quiescent, low-energy state and a proliferating, high-energy state (see Durand and Zon). Three groups (Nakada et al., Gurumurthy et al., and Gan et al.) showed that inducible loss of Lkb1, a kinase involved in linking energy status and proliferation, caused an initial transient increase in HSCs, followed by depletion of all blood cell types (pancytopenia) in mice. The transient increase in HSCs was associated with increased proliferation, indicating that in the absence of Lkb1 they were released from the quiescent state. However, ultimately the HSC population exhibited increased apoptosis and signs of genotoxic stress and cell cycle defects, such as aneuploidy, spindle defects, and increased staining for markers of DNA damage. Lkb1-deficient bone marrow cells failed to reconstitute blood cells in wild-type donor transplantation experiments, indicating that the defect in the HSC population was cell intrinsic. When nutrients are depleted, Lkb1 stimulates the activity of AMP-activated protein kinase (AMPK), which in turn inhibits the mammalian target of rapamycin complex (mTORC) that stimulates protein synthesis. However, neither rapamycin treatment to inhibit mTORC nor administration of metformin to stimulate AMPK rescued the pancytopenia associated with induced loss of Lkb1, suggesting that Lkb1 acts through other pathways to control the HSC population. The Lkb1-deficient HSCs exhibited a decline in mitochondrial membrane potential and reduced amounts of ATP, despite an increase in mitochondrial mass (thought to be a compensatory response). Lkb1-deficient HSCs exhibited altered lipid metabolism and reduced expression of genes encoding two transcriptional regulators of mitochondrial biogenesis (PGC-1α and PGC-1β). Because these cellular consequences of Lkb1 loss were limited to the stem cell population and not observed in the differentiated blood cells, it appears that the HSC population is particularly reliant on Lkb1-mediated metabolic sensing to maintain the quiescent state and respond appropriately to the increased metabolic demand required in the proliferating state.

D. Nakada, T. L. Saunders, S. J. Morrison, Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature 468, 653–658 (2010). [PubMed]

S. Gurumurthy, S. Z. Xie, B. Alagesan, J. Kim. R. Z. Yusuf, B. Saez, A. Tzatsos, F. Ozsolak, P. Milos, F. Ferrari, P. J. Park, O. S. Shirihai, D. T. Scadden. N. Bardeesy, The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature 468, 659–663 (2010). [PubMed]

B. Gan, J. Hu, S. Jiang, Y. Liu, E. Sahin, L. Zhuang, E. Fletcher-Sananikone, S. Colla, Y. A. Wang, L. Chin, R. A. DePinho, Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells. Nature 468, 701–704 (2010). [PubMed]

E. M. Durand, L. I. Zon, The blood balance. Nature 468, 644–645 (2010). [PubMed]

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