Total body irradiation causes residual bone marrow injury by induction of persistent oxidative stress in murine hematopoietic stem cells
Open accessAbstract
Ionizing radiation (IR) and/or chemotherapy causes not only acute tissue damage but also late effects including long-term (or residual) bone marrow (BM) injury. The induction of residual BM injury is primarily attributable to the induction of hematopoietic stem cell (HSC) senescence. However, the molecular mechanisms by which IR and/or chemotherapy induces HSC senescence have not been clearly defined, nor has an effective treatment been developed to ameliorate the injury. Thus, we investigated these mechanisms in this study. The results from this study show that exposure of mice to a sublethal dose of total body irradiation (TBI) induced a persistent increase in reactive oxygen species (ROS) production in HSCs only. The induction of chronic oxidative stress in HSCs was associated with sustained increases in oxidative DNA damage, DNA double-strand breaks (DSBs), inhibition of HSC clonogenic function, and induction of HSC senescence but not apoptosis. Treatment of the irradiated mice with N-acetylcysteine after TBI significantly attenuated IR-induced inhibition of HSC clonogenic function and reduction of HSC long-term engraftment after transplantation. The induction of chronic oxidative stress in HSCs by TBI is probably attributable to the up-regulation of NADPH oxidase 4 (NOX4), because irradiated HSCs expressed an increased level of NOX4, and inhibition of NOX activity with diphenylene iodonium but not apocynin significantly reduced TBI-induced increases in ROS production, oxidative DNA damage, and DNA DSBs in HSCs and dramatically improved HSC clonogenic function. These findings provide the foremost direct evidence demonstrating that TBI selectively induces chronic oxidative stress in HSCs at least in part via up-regulation of NOX4, which leads to the induction of HSC senescence and residual BM injury.
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Persistent elevation of reactive oxygen species and oxidative DNA damage are associated with increased senescence and decreased clonogenic capacity of hematopoietic stem cells.
“Wang et al. observed that persistent elevation of ROS and oxidative DNA damage are associated with increased senescence and decreased clonogenic capacity of hematopoietic stem cells (HSC) [103].”
From Ultraviolet Radiation‐Induced Skin Aging: The Role of DNA Damage and Oxidative Stress in Epidermal Stem Cell Damage Mediated Skin Aging (2016) · cites this paper as [103]
Elevated reactive oxygen species is responsible for premature aging of the stem cells of the skin.
“Although the mechanisms by which ROS act on molecular changes in ESCs in the process of skin aging are not well understood, it has been shown that elevated ROS is responsible for premature aging of the stem cells of the skin.”
From Ultraviolet Radiation‐Induced Skin Aging: The Role of DNA Damage and Oxidative Stress in Epidermal Stem Cell Damage Mediated Skin Aging (2016) · cites this paper as [103]
Previous studies suggest that IR induces HSC senescence primarily via induction of oxidative stress.
“Our previous studies suggest that IR induces HSC senescence primarily via induction of oxidative stress,9,23,30”
From Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner (2014) · cites this paper as [23]
Exposure of mice to TBI induced persistent increases in ROS production in HSC-enriched LSK cells, in part via upregulation of nicotinamide adenine dinucleotide phosphate-oxidase 4.
“exposure of mice to TBI induced persistent increases in ROS production in HSC-enriched LSK cells, in part via upregulation of nicotinamide adenine dinucleotide phosphate-oxidase 4.23”
From Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner (2014) · cites this paper as [23]
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- Authors
- Wang, Y., Liu, L., Pazhanisamy, S. K., Li, H., Meng, A., & Zhou, D.
- Affiliations
- Medical University of South Carolina (US)
- Corresponding author
- Zhou, Daohong
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2010-01
- Volume
- 48
- Issue
- 2
- Pages
- 348-356
- ISSN
- 0891-5849 (ISSN-L)
- PMC
- PMC2818724
- OpenAlex
- W2008484243
- Cited by
- 273
- References
- 47
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 14 · 2023: 13 · 2022: 10 · 2021: 12 · 2020: 20 · 2019: 19 · 2018: 27 · 2017: 21 · 2016: 13 · 2015: 25 · 2014: 19 · 2013: 23 · 2012: 22
- FWCI
- 10.27
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Medical University of South Carolina
- National Natural Science Foundation of China
- Hollings Cancer Center, Medical University of South Carolina
- National Cancer Institute (CA102558, R01CA102558, R01CA122023, R01CA078688, R01-CA086688, R01CA086860, P30CA138313)
- National Institute of Allergy and Infectious Diseases (R01AI080421)
- National Center for Research Resources (C06RR014516)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- total body irradiation, oxidative stress, reactive oxygen species, NOX4, oxidative DNA damage, DNA double-strand breaks, N-acetylcysteine, diphenyleneiodonium, apocynin, long-term engraftment
- MeSH terms
- NADPH Oxidase 4, Acetylcysteine, Animals, Bone Marrow, Cells, Cultured, DNA Damage, Female, Gene Expression Regulation, Hematopoietic Stem Cells, Male, Mice, Inbred C57BL, Onium Compounds, Radiation Injuries, Experimental, Whole-Body Irradiation, Reactive Oxygen Species, Hematopoietic Stem Cell Transplantation, Oxidative Stress, NADPH Oxidases, Transplantation Tolerance, Cell Proliferation, Mice
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