Hematopoietic Stem Cells Reversibly Switch from Dormancy to Self-Renewal during Homeostasis and Repair
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Bone marrow hematopoietic stem cells (HSCs) are crucial to maintain lifelong production of all blood cells. Although HSCs divide infrequently, it is thought that the entire HSC pool turns over every few weeks, suggesting that HSCs regularly enter and exit cell cycle. Here, we combine flow cytometry with label-retaining assays (BrdU and histone H2B-GFP) to identify a population of dormant mouse HSCs (d-HSCs) within the lin(-)Sca1+cKit+CD150+CD48(-)CD34(-) population. Computational modeling suggests that d-HSCs divide about every 145 days, or five times per lifetime. d-HSCs harbor the vast majority of multilineage long-term self-renewal activity. While they form a silent reservoir of the most potent HSCs during homeostasis, they are efficiently activated to self-renew in response to bone marrow injury or G-CSF stimulation. After re-establishment of homeostasis, activated HSCs return to dormancy, suggesting that HSCs are not stochastically entering the cell cycle but reversibly switch from dormancy to self-renewal under conditions of hematopoietic stress.
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Loss of quiescence is a major factor leading to erosion of hematopoietic stem cell self-renewal.
“Loss of quiescence is a major factor leading to erosion of HSC self-renewal (31,32).”
From <i>Txnip</i> Enhances Fitness of <i>Dnmt3a</i> -Mutant Hematopoietic Stem Cells via <i>p21</i> (2022) · cites this paper as [31]
Because many HSCs remain quiescent for much of adult life, continuing DNA damage accumulation may eventually exceed a threshold that impairs stem cell function in aged animals.
“Thus, as many HSCs remain quiescent for much of adult life54,55, the continuing accumulation of damage in these cells may eventually exceed a threshold that impairs stem cell function in aged animals.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [54]
In the mouse hematopoietic system, both cycling and quiescent HSC subpopulations were correctly predicted to be less differentiated, but only proliferative HSCs were significantly ranked above early progenitors.
“Although both cycling and quiescent hematopoietic stem cell (HSC) subpopulations (34) were correctly predicted to be less differentiated, only proliferative HSCs were significantly ranked above early progenitors (Fig. 3C).”
From Single-cell transcriptional diversity is a hallmark of developmental potential (2020) · cites this paper as [34]
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- Authors
- Wilson, A., Laurenti, E., Oser, G., van der Wath, R. C., Blanco-Bose, W., Jaworski, M., Offner, S., Dunant, C. F., Eshkind, L., Bockamp, E., Lió, P., MacDonald, H. R., & Trumpp, A.
- Affiliations
- Ludwig Cancer Research (CH)
- École Polytechnique Fédérale de Lausanne (CH)
- Johannes Gutenberg University Mainz (DE)
- German Cancer Research Center (DE)
- Corresponding author
- Trumpp, Andreas
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2008-12
- Volume
- 135
- Issue
- 6
- Pages
- 1118-1129
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2070154483
- Cited by
- 1,908
- References
- 68
- Citations by year
- 2026: 59 · 2025: 71 · 2024: 100 · 2023: 98 · 2022: 105 · 2021: 118 · 2020: 130 · 2019: 105 · 2018: 119 · 2017: 104 · 2016: 127 · 2015: 120 · 2014: 137 · 2013: 124 · 2012: 120
- FWCI
- 57.99
- Type
- journal article
- Language
- en
- Update notices
- erratum (2009-07-10)
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1689 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Cambridge University Engineering Department Publications Database (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Bradlow Foundation
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Keywords
- hematopoietic stem cells, stem cell quiescence, self-renewal, HSC quiescence, cell cycle, label-retaining cells, bromodeoxyuridine, bone marrow damage, granulocyte colony-stimulating factor, hematopoietic homeostasis, computational modeling, multilineage reconstitution
- MeSH terms
- Animals, Antigens, Differentiation, Bone Marrow, Bromouracil, Fluorouracil, Hematopoietic Stem Cells, Homeostasis, Mice, Transgenic, Uridine, Green Fluorescent Proteins, Mice, Adult Stem Cells
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