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Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells
Open accessAbstract
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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“The effect of LKB1 on HSC quiescence is cell autonomous, as shown by transplantation experiments in which LKB1-deficient HSCs are not able to rescue lethally irradiate d recipient mice118–120.”
From Molecular regulation of stem cell quiescence (2013) · cites this paper as [120]
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“upon genetic ablation of LKB1, HSC quiescence is lost and is accompanied by an increase in progenitor cell proliferation and eventual depletion of HSCs118–120”
From Molecular regulation of stem cell quiescence (2013) · cites this paper as [120]
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“the liver kinase B1 (LKB1)-adenine monophosphate-activated protein kinase (AMPK) pathway senses cellular energy levels and activates glucose uptake when necessary by inhibiting mTOR in HSCs106.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [106]
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Metadata
- Authors
- Nakada, D., Saunders, T. L., & Morrison, S. J.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of Michigan (US)
- Corresponding author
- Morrison, Sean J.
- Venue
- Nature
- Published
- 2010-12
- Volume
- 468
- Issue
- 7324
- Pages
- 653-658
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3059717
- OpenAlex
- W2049279804
- Cited by
- 524
- References
- 47
- Citations by year
- 2026: 12 · 2025: 12 · 2024: 29 · 2023: 29 · 2022: 35 · 2021: 27 · 2020: 29 · 2019: 36 · 2018: 41 · 2017: 33 · 2016: 41 · 2015: 33 · 2014: 49 · 2013: 45 · 2012: 39
- FWCI
- 23.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (CA46592, P30CA046592)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- LKB1, STK11, hematopoietic stem cells, AMPK, energy metabolism, cell cycle regulation, HSC quiescence, HSC depletion, pancytopenia, mitochondrial function, ATP levels, mitotic spindle, aneuploidy, tumor suppression, tissue regeneration, oxidative stress
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Aneuploidy, Animals, Cell Cycle, Cell Division, Cell Survival, Energy Metabolism, Enzyme Activation, Female, Hematopoietic Stem Cells, Male, Mice, Inbred C57BL, Mitochondria, Spindle Apparatus, Pancytopenia, Proteins, Regeneration, Signal Transduction, Cell Death, Protein Serine-Threonine Kinases, Gene Deletion, Centrosome, Sirolimus, Catalytic Domain, Multiprotein Complexes, Mice, AMP-Activated Protein Kinases, TOR Serine-Threonine Kinases
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