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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinases / chemistry
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AMP-Activated Protein Kinases / deficiency
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AMP-Activated Protein Kinases / genetics
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AMP-Activated Protein Kinases / metabolism
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Aneuploidy
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Animals
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Catalytic Domain / genetics
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Cell Cycle / physiology*
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Cell Death
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Cell Division
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Cell Survival
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Centrosome / pathology
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Energy Metabolism / physiology*
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Enzyme Activation
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Female
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Gene Deletion
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Hematopoietic Stem Cells / cytology*
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Hematopoietic Stem Cells / drug effects
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Hematopoietic Stem Cells / metabolism*
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Hematopoietic Stem Cells / pathology
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Male
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Mechanistic Target of Rapamycin Complex 1
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Mice
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Mice, Inbred C57BL
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Mitochondria / metabolism
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Mitochondria / pathology
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Multiprotein Complexes
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Pancytopenia / genetics
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Protein Serine-Threonine Kinases / deficiency
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Proteins / metabolism
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Regeneration
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Signal Transduction
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Sirolimus / pharmacology
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Spindle Apparatus / pathology
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TOR Serine-Threonine Kinases / metabolism
Substances
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Multiprotein Complexes
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Proteins
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mTOR protein, mouse
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Mechanistic Target of Rapamycin Complex 1
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Protein Serine-Threonine Kinases
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Stk11 protein, mouse
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TOR Serine-Threonine Kinases
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AMP-Activated Protein Kinases
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Sirolimus