Cited by 625Autophagy in Disease and TherapyHematopoietic Stem Cell TransplantationFOXO transcription factor regulation

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FOXO3A directs a protective autophagy program in haematopoietic stem cells

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Warr, Matthew R., Binnewies, Mikhail, Flach, Johanna, Reynaud, Damien, Garg, Trit, Malhotra, Ritu, Debnath, Jayanta, Passegué, Emmanuelle·2013·Nature

DOI 10.1038/nature11895PMC PMC3579002

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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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Authors: Warr, M. R., Binnewies, M., Flach, J., Reynaud, D., Garg, T., Malhotra, R., Debnath, J., & Passegué, E.
Affiliations: University of California, San Francisco (US)
ORCID: Warr, Matthew R.
Binnewies, Mikhail
Flach, Johanna
Reynaud, Damien
Debnath, Jayanta
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2013-02
Volume: 494
Issue: 7437
Pages: 323-327
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature11895
PMC: PMC3579002
OpenAlex: W2055807959
Cited by: 625
References: 40
Citations by year: 2026: 28 · 2025: 28 · 2024: 36 · 2023: 39 · 2022: 42 · 2021: 48 · 2020: 46 · 2019: 54 · 2018: 57 · 2017: 60 · 2016: 55 · 2015: 54 · 2014: 47 · 2013: 31
FWCI: 44.99
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
RePEc: Research Papers in Economics (submittedVersion)
eScholarship (California Digital Library) (submittedVersion)
Funders: Tokyo Medical and Dental University
National Institutes of Health
University of California, San Francisco
National Heart, Lung, and Blood Institute (HL092471, R01HL111266, R01HL092471)
National Cancer Institute (R01CA184014, CA126792, R01CA126792)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
Keywords: FOXO3, autophagy, hematopoietic stem cells, metabolic stress, caloric restriction, cytokine withdrawal, aging, energy crisis, HSC self-renewal
MeSH terms: Forkhead Box Protein O3, Aging, Animals, Autophagy, Cell Survival, Energy Metabolism, Food Deprivation, Gene Expression Regulation, Hematopoietic Stem Cells, Homeostasis, Mice, Inbred C57BL, Stress, Physiological, Cytokines, Cellular Senescence, Apoptosis, Caloric Restriction, Mice, Forkhead Transcription Factors

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FOXO3A directs a protective autophagy program in haematopoietic stem cells

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