Exit from dormancy provokes DNA-damage-induced attrition in haematopoietic stem cells
Abstract
Haematopoietic stem cells (HSCs) are responsible for the lifelong production of blood cells. The accumulation of DNA damage in HSCs is a hallmark of ageing and is probably a major contributing factor in age-related tissue degeneration and malignant transformation. A number of accelerated ageing syndromes are associated with defective DNA repair and genomic instability, including the most common inherited bone marrow failure syndrome, Fanconi anaemia. However, the physiological source of DNA damage in HSCs from both normal and diseased individuals remains unclear. Here we show in mice that DNA damage is a direct consequence of inducing HSCs to exit their homeostatic quiescent state in response to conditions that model physiological stress, such as infection or chronic blood loss. Repeated activation of HSCs out of their dormant state provoked the attrition of normal HSCs and, in the case of mice with a non-functional Fanconi anaemia DNA repair pathway, led to a complete collapse of the haematopoietic system, which phenocopied the highly penetrant bone marrow failure seen in Fanconi anaemia patients. Our findings establish a novel link between physiological stress and DNA damage in normal HSCs and provide a mechanistic explanation for the universal accumulation of DNA damage in HSCs during ageing and the accelerated failure of the haematopoietic system in Fanconi anaemia patients.
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Inflammation is a cardinal regulator of HSC function with many effects on HSC fate and function, including proliferation-induced DNA-damage and depletion of HSCs.
“Inflammation is a cardinal regulator of HSC function with many effects on HSC fate and function47, including proliferation-induced DNA-damage and depletion of HSCs41.”
From Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution (2023) · cites this paper as [41]
Aged HSCs accumulate signs of widespread DNA damage, including γ-H2AX foci.
“aged HSC accumulate signatures of widespread DNA damage, including g-H2AX foci.”
From Aging of hematopoietic stem cells (2018) · cites this paper as [49]
Cites
Functional Role of Type I and Type II Interferons in Antiviral Defense
Müller, U., Steinhoff, U., Reis, L. F. L., Hemmi, S., Pavlovic, J., Zinkernagel, R. M., & Aguet, M. (1994) · Science · doi:10.1126/science.8009221 · Cited by 2,453 · see citing works
Defining the Epithelial Stem Cell Niche in Skin
Tumbar, T., Guasch, G., Greco, V., Blanpain, C., Lowry, W. E., Rendl, M., & Fuchs, E. (2004) · Science · doi:10.1126/science.1092436 · Cited by 2,031 · see citing works
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., et al. (2008) · Cell · doi:10.1016/j.cell.2008.10.048 · Cited by 1,908 · see citing works
Self-citationIFNα activates dormant haematopoietic stem cells in vivo
Essers, M. A. G., Offner, S., Blanco-Bose, W. E., Waibler, Z., Kalinke, U., Duchosal, M. A., & Trumpp, A. (2009) · Nature · doi:10.1038/nature07815 · Cited by 1,368 · see citing works
Self-citationSimsek, T., Kocabas, F., Zheng, J., DeBerardinis, R. J., Mahmoud, A. I., Olson, E. N., Schneider, J. W., Zhang, C. C., & Sadek, H. A. (2010) · Cell Stem Cell · doi:10.1016/j.stem.2010.07.011 · Cited by 1,101 · see citing works
Stems Cells and the Pathways to Aging and Cancer
Rossi, D. J., Jamieson, C. H. M., & Weissman, I. L. (2008) · Cell · doi:10.1016/j.cell.2008.01.036 · Cited by 895 · see citing works
Real-time imaging of the intracellular glutathione redox potential
Gutscher, M., Pauleau, A.-L., Marty, L., Brach, T., Wabnitz, G. H., Samstag, Y., Meyer, A. J., & Dick, T. P. (2008) · Nature Methods · doi:10.1038/nmeth.1212 · Cited by 894 · see citing works
Self-citationYoshihara, H., Arai, F., Hosokawa, K., Hagiwara, T., Takubo, K., Nakamura, Y., Gomei, Y., Iwasaki, H., Matsuoka, S., Miyamoto, K., et al. (2007) · Cell stem cell · doi:10.1016/j.stem.2007.10.020 · Cited by 816 · see citing works
Takubo, K., Nagamatsu, G., Kobayashi, C. I., Nakamura‐Ishizu, A., Kobayashi, H., Ikeda, E., Goda, N., Rahimi, Y., Johnson, R. S., Soga, T., et al. (2013) · Cell stem cell · doi:10.1016/j.stem.2012.10.011 · Cited by 810 · see citing works
A 20-year perspective on the International Fanconi Anemia Registry (IFAR)
Kutler, D. I., Singh, B., Satagopan, J. M., Batish, S. D., Berwick, M., Giampietro, P. F., Hanenberg, H., & Auerbach, A. D. (2003) · Blood · doi:10.1182/blood-2002-07-2170 · Cited by 760 · see citing works
Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells
Flach, J., Bakker, S. T., Mohrin, M., Conroy, P. C., Pietras, E. M., Reynaud, D., Alvarez, S., Diolaiti, M. E., Ugarte, F., Forsberg, E. C., et al. (2014) · Nature · doi:10.1038/nature13619 · Cited by 650 · see citing works
Fluorescent Protein-Based Redox Probes
Meyer, A. J., & Dick, T. P. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.2948 · Cited by 528 · see citing works
Self-citationProximity-based Protein Thiol Oxidation by H2O2-scavenging Peroxidases
Gutscher, M., Sobotta, M. C., Wabnitz, G. H., Ballikaya, S., Meyer, A. J., Samstag, Y., & Dick, T. P. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.059246 · Cited by 459 · see citing works
Self-citationBeerman, I., Seita, J., Inlay, M. A., Weissman, I. L., & Rossi, D. J. (2014) · Cell Stem Cell · doi:10.1016/j.stem.2014.04.016 · Cited by 445 · see citing works
Hematopoietic Cytokines Can Instruct Lineage Choice
Rieger, M. A., Hoppe, P. S., Smejkal, B. M., Eitelhuber, A. C., & Schroeder, T. (2009) · Science · doi:10.1126/science.1171461 · Cited by 404 · see citing works
Self-citationDNA damage and ageing: new-age ideas for an age-old problem
Garinis, G. A., van der Horst, G. T. J., Vijg, J., & H.J. Hoeijmakers, J. (2008) · Nature Cell Biology · doi:10.1038/ncb1108-1241 · Cited by 366 · see citing works
Measuring EGSH and H2O2 with roGFP2-based redox probes
Morgan, B., Sobotta, M. C., & Dick, T. P. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.08.035 · Cited by 295 · see citing works
Self-citationWhitney, M., Royle, G., Low, M. J., Kelly, M., Axthelm, M., Reifsteck, C. A., Olson, S. D., Braun, R. E., Heinrich, M. C., Rathbun, R. K., et al. (1996) · Blood · doi:10.1182/blood.v88.1.49.bloodjournal88149 · Cited by 253 · see citing works
Whitney, M., Royle, G., Low, M. J., Kelly, M., Axthelm, M., Reifsteck, C. A., Olson, S., Braun, R. E., Heinrich, M. C., Rathbun, R. K., et al. (1996) · Blood · doi:10.1182/blood.v88.1.49.49 · Cited by 234 · see citing works
Wright, D. E., Cheshier, S. H., Wagers, A. J., Randall, T. D., Christensen, J. L., & Weissman, I. L. (2001) · Blood · doi:10.1182/blood.v97.8.2278 · Cited by 208 · see citing works
Wong, J. C. Y. (2003) · Human Molecular Genetics · doi:10.1093/hmg/ddg219 · Cited by 177 · see citing works
Haneline, L. S., Broxmeyer, H. E., Cooper, S. H., Hangoc, G., Carreau, M., Buchwald, M., & Clapp, D. W. (1998) · Blood · doi:10.1182/blood.v91.11.4092 · Cited by 171 · see citing works
Why does the bone marrow fail in Fanconi anemia?
Garaycoechea, J. I., & Patel, K. J. (2013) · Blood · doi:10.1182/blood-2013-09-427740 · Cited by 165 · see citing works
Schunck, C., Johannes, T., Varga, D., Lörch, T., & Plesch, A. (2004) · Cytogenetic and Genome Research · doi:10.1159/000077520 · Cited by 160 · see citing works
Schmezer, P. (2001) · Mutagenesis · doi:10.1093/mutage/16.1.25 · Cited by 116 · see citing works
Self-citationAltered Proliferative Response by T Lymphocytes of Ly-6A (Sca-1) Null Mice
Stanford, W. L., Haque, S., Alexander, R., Liu, X., Latour, A. M., Snodgrass, H. R., Koller, B. H., & Flood, P. M. (1997) · The Journal of Experimental Medicine · doi:10.1084/jem.186.5.705 · Cited by 113 · see citing works
Pathophysiologic Mechanisms in Acquired Aplastic Anemia
Young, N. S. (2006) · Hematology · doi:10.1182/asheducation-2006.1.72 · Cited by 100 · see citing works
The Effect of Bleeding on Hematopoietic Stem Cell Cycling and Self-Renewal
Cheshier, S. H., Prohaska, S. S., & Weissman, I. L. (2007) · Stem Cells and Development · doi:10.1089/scd.2007.0017 · Cited by 99 · see citing works
Greve, B., Bölling, T., Amler, S., Rößler, U., Gomolka, M., Mayer, C., Popanda, O., Dreffke, K., Rickinger, A., Fritz, E., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0047185 · Cited by 71 · see citing works
Self-citationCytokine-Regulated GADD45G Induces Differentiation and Lineage Selection in Hematopoietic Stem Cells
Thalheimer, F. B., Wingert, S., Giacomo, P. D., Haetscher, N., Rehage, M., Brill, B., Theis, F. J., Hennighausen, L. G., Schroeder, T., & Rieger, M. A. (2014) · Stem Cell Reports · doi:10.1016/j.stemcr.2014.05.010 · Cited by 44 · see citing works
Self-citationMilsom, M. D., Schiedlmeier, B., Bailey, J., Kim, M., Li, D., Jansen, M., Ali, A. M., Kirby, M., Baum, C., Fairbairn, L., et al. (2009) · Blood · doi:10.1182/blood-2008-09-180224 · Cited by 26 · see citing works
Self-citationGeiselhart, A., Lier, A., Walter, D., & Milsom, M. D. (2012) · Anemia · doi:10.1155/2012/265790 · Cited by 19 · see citing works
Self-citationBockamp, E., Antunes, C., Maringer, M., Heck, R., Presser, K., Beilke, S., Ohngemach, S., Alt, R., Cross, M. A., Sprengel, R., et al. (2006) · Blood · doi:10.1182/blood-2005-12-012104 · Cited by 19 · see citing works
Flagged first, then by citations
Cited by
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Mitroulis, I., Ruppova, K., Wang, B., Chen, L.-S., Grzybek, M., Grinenko, T., Eugster, A., Troullinaki, M., Palladini, A., Kourtzelis, I., et al. (2018) · Cell · doi:10.1016/j.cell.2017.11.034 · Cited by 1,100 · see citing works
Adult haematopoietic stem cell niches
Crane, G. M., Jeffery, E., & Morrison, S. J. (2017) · Nature Reviews Immunology · doi:10.1038/nri.2017.53 · Cited by 712 · see citing works
Aging of hematopoietic stem cells
de Haan, G., & Lazare, S. S. (2018) · Blood · doi:10.1182/blood-2017-06-746412 · Cited by 432 · see citing works
Vitamin A-Retinoic Acid Signaling Regulates Hematopoietic Stem Cell Dormancy
Cabezas-Wallscheid, N., Buettner, F., Sommerkamp, P., Klimmeck, D., Ladel, L., Thalheimer, F. B., Pastor-Flores, D., Roma, L. P., Renders, S., Zeisberger, P., et al. (2017) · Cell · doi:10.1016/j.cell.2017.04.018 · Cited by 454 · see citing works
Self-citationInflammation: a key regulator of hematopoietic stem cell fate in health and disease
Pietras, E. M. (2017) · Blood · doi:10.1182/blood-2017-06-780882 · Cited by 417 · see citing works
Quiescence Modulates Stem Cell Maintenance and Regenerative Capacity in the Aging Brain
Kalamakis, G., Brüne, D., Ravichandran, S., Bolz, J., Fan, W., Ziebell, F., Stiehl, T., Catalá-Martinez, F., Kupke, J., Zhao, S., et al. (2019) · Cell · doi:10.1016/j.cell.2019.01.040 · Cited by 399 · see citing works
Self-citationVitale, I., Manic, G., De Maria, R., Kroemer, G., & Galluzzi, L. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.04.006 · Cited by 361 · see citing works
Hematopoietic Stem Cells Are the Major Source of Multilineage Hematopoiesis in Adult Animals
Sawai, C. M., Babovic, S., Upadhaya, S., Knapp, D. J. H. F., Lavin, Y., Lau, C. M., Goloborodko, A., Feng, J., Fujisaki, J., Ding, L., et al. (2016) · Immunity · doi:10.1016/j.immuni.2016.08.007 · Cited by 381 · see citing works
Zambetti, N. A., Ping, Z., Chen, S., Kenswil, K. J. G., Mylona, M. A., Sanders, M. A., Hoogenboezem, R. M., Bindels, E. M. J., Adisty, M. N., Van Strien, P. M. H., et al. (2016) · Cell stem cell · doi:10.1016/j.stem.2016.08.021 · Cited by 342 · see citing works
Bogeska, R., Mikecin, A.-M., Kaschutnig, P., Fawaz, M., Büchler-Schäff, M., Le, D., Ganuza, M., Vollmer, A., Paffenholz, S. V., Asada, N., et al. (2022) · Cell Stem Cell · doi:10.1016/j.stem.2022.06.012 · Cited by 299 · see citing works
Self-citationHematopoietic stem cells count and remember self-renewal divisions
Bernitz, J. M., Kim, H. S., MacArthur, B., Sieburg, H., & Moore, K. (2016) · Cell · doi:10.1016/j.cell.2016.10.022 · Cited by 285 · see citing works
Cellular and epigenetic drivers of stem cell ageing
Ermolaeva, M., Neri, F., Ori, A., & Rudolph, K. L. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0020-3 · Cited by 272 · see citing works
Chaperone-mediated autophagy sustains haematopoietic stem-cell function
Dong, S., Wang, Q., Kao, Y.-R., Diaz, A., Tasset, I., Kaushik, S., Thiruthuvanathan, V., Zintiridou, A., Nieves, E., Dzieciatkowska, M., et al. (2021) · Nature · doi:10.1038/s41586-020-03129-z · Cited by 275 · see citing works
Do DNA Double-Strand Breaks Drive Aging?
White, R. R., & Vijg, J. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.08.004 · Cited by 232 · see citing works
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Barreyro, L., Chlon, T. M., & Starczynowski, D. T. (2018) · Blood · doi:10.1182/blood-2018-03-784116 · Cited by 226 · see citing works
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Yun, M. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms161025392 · Cited by 216 · see citing works
Rodriguez-Meira, A., Norfo, R., Wen, S., Chédeville, A. L., Rahman, H., O’Sullivan, J., Wang, G., Louka, E., Kretzschmar, W. W., Paterson, A., et al. (2023) · Nature Genetics · doi:10.1038/s41588-023-01480-1 · Cited by 158 · see citing works
Tissue-specific designs of stem cell hierarchies
Visvader, J. E., & Clevers, H. (2016) · Nature Cell Biology · doi:10.1038/ncb3332 · Cited by 150 · see citing works
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Henry, C. J., Casás-Selves, M., Kim, J., Zaberezhnyy, V., Aghili, L., Daniel, A. E., Jimenez, L., Azam, T., McNamee, E. N., Clambey, E. T., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci83024 · Cited by 148 · see citing works
Paradoxical changes in innate immunity in aging: recent progress and new directions
Montgomery, R. R., & Shaw, A. C. (2015) · Journal of Leukocyte Biology · doi:10.1189/jlb.5mr0315-104r · Cited by 147 · see citing works
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Saçma, M., Pospiech, J., Bogeska, R., de Back, W., Mallm, J.-P., Sakk, V., Soller, K., Marka, G., Vollmer, A., Karns, R., et al. (2019) · Nature Cell Biology · doi:10.1038/s41556-019-0418-y · Cited by 133 · see citing works
Self-citationTang, D., Tao, S., Chen, Z., Koliesnik, I. O., Calmes, P. G., Hoerr, V., Han, B., Gebert, N., Zörnig, M., Löffler, B., et al. (2016) · Journal of Experimental Medicine · doi:10.1084/jem.20151100 · Cited by 133 · see citing works
The role of interferon-gamma in hematopoietic stem cell development, homeostasis, and disease
Morales-Mantilla, D. E., & King, K. Y. (2018) · Current Stem Cell Reports · doi:10.1007/s40778-018-0139-3 · Cited by 99 · see citing works
Kruta, M., Sunshine, M. J., Chua, B. A., Fu, Y., Chawla, A., Dillingham, C. H., Hidalgo San Jose, L., De Jong, B., Zhou, F. J., & Signer, R. A. J. (2021) · Cell Stem Cell · doi:10.1016/j.stem.2021.07.009 · Cited by 100 · see citing works
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Nakahara, F., Borger, D. K., Wei, Q., Pinho, S., Maryanovich, M., Zahalka, A. H., Suzuki, M., Cruz, C. D., Wang, Z., Xu, C., et al. (2019) · Nature Cell Biology · doi:10.1038/s41556-019-0308-3 · Cited by 99 · see citing works
PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress
Chavez, J. S., Rabe, J. L., Loeffler, D., Higa, K. C., Hernandez, G., Mills, T. S., Ahmed, N., Gessner, R. L., Ke, Z., Idler, B. M., et al. (2021) · Journal of Experimental Medicine · doi:10.1084/jem.20201169 · Cited by 91 · see citing works
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Piras, F., Riba, M., Petrillo, C., Lazarevic, D., Cuccovillo, I., Bartolaccini, S., Stupka, E., Gentner, B., Cittaro, D., Naldini, L., et al. (2017) · EMBO Molecular Medicine · doi:10.15252/emmm.201707922 · Cited by 75 · see citing works
Gutierrez-Martinez, P., Hogdal, L., Nagai, M., Kruta, M., Singh, R., Sarosiek, K., Nussenzweig, A., Beerman, I., Letai, A., & Rossi, D. J. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0054-y · Cited by 60 · see citing works
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Rabe, J. L., Hernandez, G., Chavez, J. S., Mills, T. S., Nerlov, C., & Pietras, E. M. (2020) · Experimental Hematology · doi:10.1016/j.exphem.2019.12.003 · Cited by 49 · see citing works
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Barghouth, P. G., Thiruvalluvan, M., LeGro, M., & Oviedo, N. J. (2019) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2018.04.013 · Cited by 48 · see citing works
Technical considerations for the use of CRISPR/Cas9 in hematology research
Gundry, M. C., Dever, D. P., Yudovich, D., Bauer, D. E., Haas, S., Wilkinson, A. C., & Singbrant, S. (2017) · Experimental Hematology · doi:10.1016/j.exphem.2017.07.006 · Cited by 26 · see citing works
Arai, F., Stumpf, P. S., Ikushima, Y. M., Hosokawa, K., Roch, A., Lutolf, M. P., Suda, T., & MacArthur, B. D. (2020) · Cell Systems · doi:10.1016/j.cels.2020.11.004 · Cited by 19 · see citing works
G2 arrest primes hematopoietic stem cells for megakaryopoiesis
Garyn, C. M., Bover, O., Murray, J. W., Ma, J., Salas-Briceno, K., Ross, S. R., & Snoeck, H.-W. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114388 · Cited by 14 · see citing works
Proliferation: Driver of HSC aging phenotypes?
Yanai, H., & Beerman, I. (2020) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2020.111331 · Cited by 9 · see citing works
- Authors
- Walter, D., Lier, A., Geiselhart, A., Thalheimer, F. B., Huntscha, S., Sobotta, M. C., Moehrle, B., Brocks, D., Bayindir, I., Kaschutnig, P., Muedder, K., Klein, C., Jauch, A., Schroeder, T., Geiger, H., Dick, T. P., Holland-Letz, T., Schmezer, P., Lane, S. W., Rieger, M. A., Essers, M. A. G., Williams, D. A., Trumpp, A., & Milsom, M. D.
- Affiliations
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (DE)
- German Cancer Research Center (DE)
- Goethe University Frankfurt (DE)
- Universität Ulm (DE)
- Heidelberg University (DE)
- ETH Zurich (CH)
- Cincinnati Children's Hospital Medical Center (US)
- The University of Queensland (AU)
- Boston Children's Hospital (US)
- Corresponding author
- Milsom, Michael D.
- ORCID
- Venue
- Nature
- Published
- 2015-02-18
- Volume
- 520
- Issue
- 7548
- Pages
- 549-552
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1980052833
- Cited by
- 619
- References
- 33
- Citations by year
- 2026: 23 · 2025: 47 · 2024: 48 · 2023: 63 · 2022: 47 · 2021: 61 · 2020: 60 · 2019: 47 · 2018: 57 · 2017: 65 · 2016: 67 · 2015: 33
- FWCI
- 58.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Keywords
- hematopoietic stem cells, DNA damage, quiescence exit, Fanconi anaemia, bone marrow failure, accelerated aging, DNA repair, aging, physiological stress, chronic blood loss, infection, genomic instability
- MeSH terms
- Animals, Bone Marrow, Cell Cycle, DNA Damage, Fanconi Anemia, Hematopoietic Stem Cells, Stress, Physiological, Cell Death, Reactive Oxygen Species, Cell Proliferation, Mice
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