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Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells

Abstract

Little is known about metabolic regulation in stem cells and how this modulates tissue regeneration or tumour suppression. We studied the Lkb1 tumour suppressor and its substrate AMP-activated protein kinase (AMPK), kinases that coordinate metabolism with cell growth. Deletion of the Lkb1 (also called Stk11) gene in mice caused increased haematopoietic stem cell (HSC) division, rapid HSC depletion and pancytopenia. HSCs depended more acutely on Lkb1 for cell-cycle regulation and survival than many other haematopoietic cells. HSC depletion did not depend on mTOR activation or oxidative stress. Lkb1-deficient HSCs, but not myeloid progenitors, had reduced mitochondrial membrane potential and ATP levels. HSCs deficient for two catalytic α-subunits of AMPK (AMPK-deficient HSCs) showed similar changes in mitochondrial function but remained able to reconstitute irradiated mice. Lkb1-deficient HSCs, but not AMPK-deficient HSCs, exhibited defects in centrosomes and mitotic spindles in culture, and became aneuploid. Lkb1 is therefore required for HSC maintenance through AMPK-dependent and AMPK-independent mechanisms, revealing differences in metabolic and cell-cycle regulation between HSCs and some other haematopoietic progenitors.

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Figure 1: Lkb1 deletion causes HSCs to go into cycle before being depleted.
Figure 2: Lkb1 -deficient HSCs have a cell-autonomous defect in their ability to reconstitute irradiated mice and to form colonies in culture.
Figure 3: AMPK signalling requires Lkb1 in HSCs/MPPs but HSC depletion could not be rescued with rapamycin.
Figure 4: AMPK deficiency partially phenocopies the mitochondrial defects but not the HSC depletion observed after Lkb1 deletion.
Figure 5: Lkb1 -deficient HSCs exhibit defects in mitotic spindles, aneuploidy and cell death.

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Acknowledgements

This work was supported by the Howard Hughes Medical Institute. Flow cytometry was partially supported by the University of Michigan (UM) Comprehensive Cancer National Institutes of Health (NIH) CA46592. D.N. was supported by a postdoctoral fellowship from the Japan Society for the Promotion of Science. We thank A. Prendergast and C. Sifuentes for technical assistance; E. Hughes and the UM Transgenic Animal Model Core for help generating Lkb1fl mice; D. Adams and M. White for flow cytometry; E. Smith for antibody production; C. Mountford, S. Grove and R. Coolon for mouse colony management; and L. Cantley and C. Thompson for discussions.

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D.N. performed all experiments. T.L.S. helped to design and generate the Lkb1fl mice. D.N. and S.J.M. designed and interpreted all experiments and wrote the paper.

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Correspondence to Sean J. Morrison.

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The authors declare no competing financial interests.

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Nakada, D., Saunders, T. & Morrison, S. Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature 468, 653–658 (2010). https://doi.org/10.1038/nature09571

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