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FOXO3A directs a protective autophagy program in haematopoietic stem cells

Nature volume 494, pages 323–327 (2013)Cite this article

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Abstract

Blood production is ensured by rare, self-renewing haematopoietic stem cells (HSCs). How HSCs accommodate the diverse cellular stresses associated with their life-long activity remains elusive. Here we identify autophagy as an essential mechanism protecting HSCs from metabolic stress. We show that mouse HSCs, in contrast to their short-lived myeloid progeny, robustly induce autophagy after ex vivo cytokine withdrawal and in vivo calorie restriction. We demonstrate that FOXO3A is critical to maintain a gene expression program that poises HSCs for rapid induction of autophagy upon starvation. Notably, we find that old HSCs retain an intact FOXO3A-driven pro-autophagy gene program, and that ongoing autophagy is needed to mitigate an energy crisis and allow their survival. Our results demonstrate that autophagy is essential for the life-long maintenance of the HSC compartment and for supporting an old, failing blood system.

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Figure 1: HSCs induce autophagy after metabolic stress.
Figure 2: Autophagy protects HSCs from starvation-induced apoptosis.
Figure 3: FOXO3A poises HSCs for rapid autophagy induction.
Figure 4: Ongoing autophagy in old HSCs.
Figure 5: Ongoing autophagy is essential for the continued survival of old HSCs.

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Acknowledgements

We thank A. Brunet for Foxo3a−/− mice, S. Oakes for Bak−/−Baxfl/fl mice, N. Mizushima for GFP-LC3 transgenic mice, J. Wong for electron microscopy analyses, M. Kissner for management of our Flow Cytometry Core Facility, and all members of the Passegué, particularly E. Pietras, and Debnath laboratories for critical insights and suggestions. M.R.W. is an LLS Special Fellow. This work was supported by a Culpepper Scholar Award (Partnership for Cures) and NIH grant CA126792 to J.D., and a CIRM New Faculty Award and NIH grant HL092471 to E.P.

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Authors and Affiliations

  1. Department of Medicine, Division of Hematology/Oncology, The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California San Francisco, San Francisco, 94143, California, USA

    Matthew R. Warr, Mikhail Binnewies, Johanna Flach, Damien Reynaud, Trit Garg & Emmanuelle Passegué

  2. Department of Pathology, University of California, San Francisco, 94143, California, USA

    Ritu Malhotra & Jayanta Debnath

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  1. Matthew R. Warr
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Contributions

M.R.W., M.B., J.F., D.R. and T.G. performed all of the experiments. R.M. and J.D. generated the Atg12fl/fl mice. M.R.W., M.B., J.D. and E.P. designed the experiments and interpreted the results. M.R.W. and E.P. wrote the manuscript.

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Correspondence to Emmanuelle Passegué.

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Warr, M., Binnewies, M., Flach, J. et al. FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature 494, 323–327 (2013). https://doi.org/10.1038/nature11895

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