FOXO3A directs a protective autophagy program in haematopoietic stem cells

Matthew R. Warr, Mikhail Binnewies, Johanna Flach, Damien Reynaud, Trit Garg, Ritu Malhotra, Jayanta Debnath and Emmanuelle Passegué ()
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Matthew R. Warr: The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California San Francisco
Mikhail Binnewies: The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California San Francisco
Johanna Flach: The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California San Francisco
Damien Reynaud: The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California San Francisco
Trit Garg: The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California San Francisco
Ritu Malhotra: University of California
Jayanta Debnath: University of California
Emmanuelle Passegué: The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California San Francisco

Nature, 2013, vol. 494, issue 7437, 323-327

Abstract: 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.

Date: 2013
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DOI: 10.1038/nature11895

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