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Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells

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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Figure 1: Lkb1 deletion leads to a severe pancytopenia phenotype.
Figure 2: Lkb1 ablation results in reduced HSC reserves and decreased repopulating potential.
Figure 3: Lkb1 regulation of haematopoiesis is Tsc–mTORC1-independent.
Figure 4: Lkb1 deletion diminishes mitochondrial biogenesis and energy production in the haematopoietic system.

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Gene Expression Omnibus

Data deposits

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

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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.

Corresponding author

Correspondence to Ronald A. DePinho.

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The authors declare no competing financial interests.

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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

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