FOXO3A directs a protective autophagy program in haematopoietic stem cells
Open accessAbstract
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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Autophagy induction by FoxO3A is an essential mechanism that protects HSCs from metabolic stress in aging.
“Warr et al., who reported autophagy induction by FoxO3A to be an essential mechanism that protects HSCs from metabolic stress in aging76.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [76]
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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)
- Venue
- Nature
- Published
- 2013-02
- Volume
- 494
- Issue
- 7437
- Pages
- 323-327
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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
- Health Sciences › Medicine › Epidemiology › 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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