title: 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.
authors: The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Medicine, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California 94143, USA.
authors: Matthew R
authors: MR
authors: Warr
authors: Mikhail
authors: M
authors: Binnewies
authors: Johanna
authors: J
authors: Flach
authors: Damien
authors: D
authors: Reynaud
authors: Trit
authors: T
authors: Garg
authors: Ritu
authors: R
authors: Malhotra
authors: Jayanta
authors: J
authors: Debnath
authors: Emmanuelle
authors: E
authors: Passegué
mesh_terms: D000375:Aging; D000818:Animals; D017209:Apoptosis; D001343:Autophagy / Q000235:genetics*; D031204:Caloric Restriction; D002470:Cell Survival / Q000235:genetics; D016922:Cellular Senescence; D016207:Cytokines / Q000172:deficiency / Q000378:metabolism; D004734:Energy Metabolism / Q000235:genetics*; D005508:Food Deprivation; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006706:Homeostasis; D051379:Mice; D008810:Mice, Inbred C57BL; D013312:Stress, Physiological / Q000235:genetics*
chemical_list: D016207:Cytokines; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse
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