Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells (original) (raw)
- Letter
- Published: 01 December 2010
- Jian Hu1,2,3,
- Shan Jiang1,2,3,
- Yingchun Liu1,2,3,
- Ergün Sahin1,2,3,
- Li Zhuang1,2,3,
- Eliot Fletcher-Sananikone1,2,3,
- Simona Colla1,2,3,
- Y. Alan Wang1,2,3,
- Lynda Chin1,2,4 &
- …
- Ronald A. DePinho1,2,3
Nature volume 468, pages 701–704 (2010)Cite this article
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Abstract
The capacity to fine-tune cellular bioenergetics with the demands of stem-cell maintenance and regeneration is central to normal development and ageing, and to organismal survival during periods of acute stress. How energy metabolism and stem-cell homeostatic processes are coordinated is not well understood. Lkb1 acts as an evolutionarily conserved regulator of cellular energy metabolism in eukaryotic cells and functions as the major upstream kinase to phosphorylate AMP-activated protein kinase (AMPK) and 12 other AMPK-related kinases1,2,3. Whether Lkb1 regulates stem-cell maintenance remains unknown. Here we show that Lkb1 has an essential role in haematopoietic stem cell (HSC) homeostasis. We demonstrate that ablation of Lkb1 in adult mice results in severe pancytopenia and subsequent lethality. Loss of Lkb1 leads to impaired survival and escape from quiescence of HSCs, resulting in exhaustion of the HSC pool and a marked reduction of HSC repopulating potential in vivo. Lkb1 deletion has an impact on cell proliferation in HSCs, but not on more committed compartments, pointing to context-specific functions for Lkb1 in haematopoiesis. The adverse impact of Lkb1 deletion on haematopoiesis was predominantly cell-autonomous and mTOR complex 1 (mTORC1)-independent, and involves multiple mechanisms converging on mitochondrial apoptosis and possibly downregulation of PGC-1 coactivators and their transcriptional network, which have critical roles in mitochondrial biogenesis and function. Thus, Lkb1 serves as an essential regulator of HSCs and haematopoiesis, and more generally, points to the critical importance of coupling energy metabolism and stem-cell homeostasis.
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Gene Expression Omnibus
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Completed microarray data are deposited on the GEO website under super series accession number GSE24765.
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Acknowledgements
We are grateful to A. Berns for providing the Rosa26-creERt2 mouse strain. We are also grateful to S. Zhou for assistance in the animal facility and C. Lim for assistance with genotyping. We thank S. Lazo-Kallanian, J. Daley and P. Schow for assistance with flow cytometry. We also thank N. Bardeesy and S. Morrison for communicating unpublished information; A. Stegh for comments on apoptosis; and D. Nakada for western blotting protocol from sorted HSCs. This research was supported by U01CA141508 (R.A.D. and L.C.), R21CA135057 (R.A.D. and B.G.) and DOD TSCRP Career Transition Award (TS093049) (B.G.). B.G. and J.H. are the Research Fellows of the Leukemia and Lymphoma Society. Y.A.W. is supported by Multiple Myeloma Research Foundation. R.A.D. was supported by an American Cancer Society Research Professorship and the Robert A. and Renee E. Belfer Foundation.
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Authors and Affiliations
- Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA
Boyi Gan, Jian Hu, Shan Jiang, Yingchun Liu, Ergün Sahin, Li Zhuang, Eliot Fletcher-Sananikone, Simona Colla, Y. Alan Wang, Lynda Chin & Ronald A. DePinho - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA
Boyi Gan, Jian Hu, Shan Jiang, Yingchun Liu, Ergün Sahin, Li Zhuang, Eliot Fletcher-Sananikone, Simona Colla, Y. Alan Wang, Lynda Chin & Ronald A. DePinho - Department of Medicine and Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA
Boyi Gan, Jian Hu, Shan Jiang, Yingchun Liu, Ergün Sahin, Li Zhuang, Eliot Fletcher-Sananikone, Simona Colla, Y. Alan Wang & Ronald A. DePinho - Department of Dermatology, Harvard Medical School, Boston, 02115, Massachusetts, USA
Lynda Chin
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Contributions
B.G. and R.A.D. designed the experiments, interpreted the data and wrote the manuscript. B.G., S.J., J.H., L.Z. and E.F.-S. performed experiments. Y.L. and L.C. conducted the microarray and promoter analyses. E.S. and S.C. contributed reagents. L.C. and Y.A.W. contributed to the writing of the manuscript.
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Correspondence toRonald A. DePinho.
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Gan, B., Hu, J., Jiang, S. et al. Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells.Nature 468, 701–704 (2010). https://doi.org/10.1038/nature09595
- Received: 24 April 2010
- Accepted: 19 October 2010
- Published: 01 December 2010
- Issue Date: 02 December 2010
- DOI: https://doi.org/10.1038/nature09595
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Editorial Summary
Lkb1 promotes haematopoietic stem cell survival
Haematopoietic stem cells are very sensitive to energetic and oxidative stress, and modulation of the balance between their quiescence and proliferation is needed to respond to metabolic stress while preserving their long-term regenerative capacity. Three new studies show that the tumour suppressor and metabolic sensor Lkb1 has a crucial role in maintaining energy homeostasis in haematopoietic cells. Lkb1 is shown to be necessary for cell-cycle regulation as well as for energy homeostasis, and haematopoietic stem cells depend more acutely on Lkb1 than any other haematopoietic cells.