Publication Date:
2013-02-08
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3579002/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3579002/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Warr, Matthew R -- Binnewies, Mikhail -- Flach, Johanna -- Reynaud, Damien -- Garg, Trit -- Malhotra, Ritu -- Debnath, Jayanta -- Passegue, Emmanuelle -- CA126792/CA/NCI NIH HHS/ -- HL092471/HL/NHLBI NIH HHS/ -- R01 CA126792/CA/NCI NIH HHS/ -- R01 CA184014/CA/NCI NIH HHS/ -- R01 HL111266/HL/NHLBI NIH HHS/ -- England -- Nature. 2013 Feb 21;494(7437):323-7. doi: 10.1038/nature11895. Epub 2013 Feb 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23389440" target="_blank"〉PubMed〈/a〉
Keywords:
Aging
;
Animals
;
Apoptosis
;
Autophagy/*genetics
;
Caloric Restriction
;
Cell Aging
;
Cell Survival/genetics
;
Cytokines/deficiency/metabolism
;
Energy Metabolism/*genetics
;
Food Deprivation
;
Forkhead Transcription Factors/*metabolism
;
*Gene Expression Regulation
;
Hematopoietic Stem Cells/*cytology/*metabolism
;
Homeostasis
;
Mice
;
Mice, Inbred C57BL
;
Stress, Physiological/*genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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