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Inflammatory exposure drives long-lived impairment of hematopoietic stem cell self-renewal activity and accelerated aging
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Abstract
Hematopoietic stem cells (HSCs) mediate regeneration of the hematopoietic system following injury, such as following infection or inflammation. These challenges impair HSC function, but whether this functional impairment extends beyond the duration of inflammatory exposure is unknown. Unexpectedly, we observed an irreversible depletion of functional HSCs following challenge with inflammation or bacterial infection, with no evidence of any recovery up to 1 year afterward. HSCs from challenged mice demonstrated multiple cellular and molecular features of accelerated aging and developed clinically relevant blood and bone marrow phenotypes not normally observed in aged laboratory mice but commonly seen in elderly humans. In vivo HSC self-renewal divisions were absent or extremely rare during both challenge and recovery periods. The progressive, irreversible attrition of HSC function demonstrates that temporally discrete inflammatory events elicit a cumulative inhibitory effect on HSCs. This work positions early/mid-life inflammation as a mediator of lifelong defects in tissue maintenance and regeneration.
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“Moreover, Bogeska et al. showed that inflammatory exposure induces long-term impairment of HSC self-renewal and accelerates their functional aging, contributing to persistent immune dysregulation [83].”
From Chronic Stress and Autoimmunity: The Role of HPA Axis and Cortisol Dysregulation (2025) · cites this paper as [83]
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“while repetitive sterile inflammation did not result in major gene expression changes, it resulted in hypomethylation of promoters of inflammatory (particularly interferon) response genes, leading them to conclude that self-renewal is epigenetically regulated in this model.”
From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [65]
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“Inflammation drives impaired self-renewal activity and accelerates aging of HSCs. Exposure to inflammatory stimuli during the early to mid-life stages in mice can lead to the eventual development of peripheral blood hemocytopenia, bone marrow (BM) cytopenia, and BM adipocyte accumulation, features that together constitute typical features of hematopoiesis in the elderly.17”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [17]
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“Chronic pro-inflammatory signaling due to chronic infections or repetitive sterile inflammation, however, has been shown to be detrimental to HSPC self-renewal, promoting loss of quiescence and differentiation [61–65].”
From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [65]
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“the authors showed that the demise of the functional stem cell population was not due to systemic inhibitory effects of inflammation on hematopoiesis but was due to increased proliferation of HSPCs, as label-retaining long-term HSPCs did not lose their repopulating capacity with chronic inflammation [65].”
From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [65]
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“One possible source could be many pro-inflammatory SASP factors which are released from senescent cells present in aged peripheral tissues (Fujino et al. 2022; Bogeska et al. 2022).”
Chen, Z., Mao, Z., Tang, W., Shi, Y., Liu, J., & You, Y. (2025) · Translational Neurodegeneration · doi:10.1186/s40035-025-00517-1 · Cited by 27
“5) [79, 158, 163–165].”
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“33 For example, recent work has shown that in fl ammatory exposures create long-term impairment of HSC self-renewal and accelerate hematopoietic aging, 37 and reduce the fi tness of B-cell progenitors, creating an environment that selects for cells harboring oncogenic mutations.”
Self-citationLinking cell cycle to hematopoietic stem cell fate decisions
Treichel, S., & Filippi, M. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1231735 · Cited by 20
“Amodel where HSCs replicate into gradually less functional progeny has been shown to occur under mild inflammatory conditions (Qiu et al., 2014; Bernitz et al., 2016; Bogeska et al., 2022).”
BackgroundBeyond “to divide or not to divide”: Kinetics matters in hematopoietic stem cells
Johnson, C., Belluschi, S., & Laurenti, E. (2020) · Experimental Hematology · doi:10.1016/j.exphem.2020.11.003 · Cited by 18
Suppression of thrombospondin-1–mediated inflammaging prolongs hematopoietic health span
Ramalingam, P., Gutkin, M. C., Poulos, M. G., Winiarski, A., Smith, A., Carter, C., Doughty, C., Tillery, T., Redmond, D., Freire, A. G., et al. (2025) · Science Immunology · doi:10.1126/sciimmunol.ads1556 · Cited by 17
Acute and Chronic Tnf-α-Induced Effects on Hematopoietic Stem Cells are Fully Reversible
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“Similarly, chronic polyinosinic:polycytidylic acid (pI:pC) stimulation reduced the repopulating capacity of HSCs, albeit without exhaustion of HSCs in the primary hosts.(12,13) By contrast, the impaired HSC repopulation ability after chronic stimulation with IL-1 could be fully restored upon removal of the stimulus an…”
BackgroundInflammation in myelodysplastic syndrome pathogenesis
Rodríguez‐Sevilla, J. J., & Colla, S. (2024) · Seminars in Hematology · doi:10.1053/j.seminhematol.2024.09.005 · Cited by 20
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The Quest for Eternal Youth: Hallmarks of Aging and Rejuvenating Therapeutic Strategies
Nunkoo, V. S., Cristian, A., Jurcău, A., Diaconu, R. G., & Jurcău, M. C. (2024) · Biomedicines · doi:10.3390/biomedicines12112540 · Cited by 15
Bone marrow niches for hematopoietic stem cells in homeostasis and aging
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Human haematopoietic stem cells remember inflammatory stress
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“Finally, as HSC-iM enrichment can reflect the systemic level of inflammation in unhealthy individuals, some of the disease correlations attributed to CH status in current literature may potentially reflect survivorship bias of an earlier HSC-iM-driven inflammatory state 1,4 .”
Cellular stress and epigenetic regulation in adult stem cells
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“In another study, fi ndings reveal that such impairments can be irreversible, with no recovery observed even after a year (108).”
BackgroundHow stem cells respond to infection, inflammation and ageing
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“3).”
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“Recently, it has been found that long-term stimulation by chronic inflammation causes a significant decrease in the proliferative capacity of hematopoietic stem cells, the origin of immune cells, resulting in accumulative and irreversible functional damage and long-term suppressive effects on hematopoiesis, further co…”
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“Inflammation is a key insult driving HSPC injury and inhibition of systemic inflammation confer protection against radiation damage [42, 43].”
Single-cell time series analysis reveals the dynamics of HSPC response to inflammation
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“This indicates irreversible changes that leave a mark in the activated cells (Bogeska et al, 2022).”
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Hematopoietic stem cell a reservoir of innate immune memory
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“A recent work shows that inflammation insult, even in the early lifetime, causes permanent impairment and premature aging of HSCs (Bogeska et al., 2022).”
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Restoring resident tissue macrophages to combat aging and cancer
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From complexity to clarity: aging bone marrow niche in bone and blood regeneration and malignancy
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“Inflammatory stimulation of mice in early to middle age results in eventual peripheral haemocytopenia, bone marrow cytopenia, and build-up of bone marrow adipocytes, which together constitute typical features of hematopoiesis in elderly humans [16].”
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“Prolonged exposure to chronic inflammation exacerbates HSC senescence, further impairing their function [12,13].”
Metadata
- Authors
- Bogeska, R., Mikecin, A.-M., Kaschutnig, P., Fawaz, M., Büchler-Schäff, M., Le, D., Ganuza, M., Vollmer, A., Paffenholz, S. V., Asada, N., Rodriguez-Correa, E., Frauhammer, F., Buettner, F., Ball, M., Knoch, J., Stäble, S., Walter, D., Petri, A., Carreño-Gonzalez, M. J., Wagner, V., Brors, B., Haas, S., Lipka, D. B., Essers, M. A. G., Weru, V., Holland-Letz, T., Mallm, J.-P., Rippe, K., Krämer, S., Schlesner, M., McKinney Freeman, S., Florian, M. C., King, K. Y., Frenette, P. S., Rieger, M. A., & Milsom, M. D.
- Affiliations
- German Cancer Research Center (DE)
- University Hospital Frankfurt (DE)
- Baylor College of Medicine (US)
- St. Jude Children's Research Hospital (US)
- Universität Ulm (DE)
- Albert Einstein College of Medicine (US)
- University of Augsburg (DE)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- Goethe University Frankfurt (DE)
- Corresponding author
- Milsom, Michael D.
- ORCID
- Bogeska, Ruzhica
- Mikecin, Ana-Matea
- Le, Duy
- Ganuza, Miguel
- Asada, Noboru
- Rodriguez-Correa, Esther
- Buettner, Florian
- Stäble, Sina
- Carreño-Gonzalez, Martha J.
- Brors, Benedikt
- Haas, Simon
- Lipka, Daniel B.
- Essers, Marieke A.G.
- Weru, Vivienn
- Mallm, Jan-Philipp
- Rippe, Karsten
- Schlesner, Matthias
- Florian, Maria Carolina
- King, Katherine Y.
- Frenette, Paul S.
- Rieger, Michael A.
- Milsom, Michael D.
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2022-08
- Volume
- 29
- Issue
- 8
- Pages
- 1273-1284.e8
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC9357150
- OpenAlex
- W4286254590
- Cited by
- 299
- References
- 66
- Citations by year
- 2026: 67 · 2025: 88 · 2024: 56 · 2023: 60 · 2022: 16
- FWCI
- 40.12
- Type
- journal article
- Language
- en
- 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, 368 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 stem cell (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion)
- OPUS (Augsburg University) (submittedVersion, cc-by-nc-nd)
- Funders
- Deutsches Krebsforschungszentrum
- Medical Research Council (MR/V009222/1)
- National Heart, Lung, and Blood Institute (F31HL154661, R35HL155672)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK112976, R01DK056638)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
- Health Sciences › Medicine › Hematology › Blood disorders and treatments
- Keywords
- hematopoietic stem cells, HSC self-renewal, inflammation, bacterial infection, accelerated aging, HSC depletion, bone marrow aging, tissue regeneration
- MeSH terms
- Aged, Aging, Animals, Bone Marrow, Hematopoiesis, Hematopoietic Stem Cells, Humans, Inflammation, Mice
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