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FOXO3A directs a protective autophagy program in haematopoietic stem cells.

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.

SUBMITTER: Warr MR

PROVIDER: S-EPMC3579002 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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FOXO3A directs a protective autophagy program in haematopoietic stem cells.

Warr Matthew R MR Binnewies Mikhail M Flach Johanna J Reynaud Damien D Garg Trit T Malhotra Ritu R Debnath Jayanta J Passegué Emmanuelle E

Nature 20130206 7437

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 main ...[more]

PMID: 23389440

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