Cited by 273Effects of Radiation ExposureHematopoietic Stem Cell TransplantationRedox biology and oxidative stress

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Total body irradiation causes residual bone marrow injury by induction of persistent oxidative stress in murine hematopoietic stem cells

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Wang, Yong, Liu, Lingbo, Pazhanisamy, Senthil K., Li, Hongliang, Meng, Aimin, Zhou, Daohong·2010·Free Radical Biology and Medicine

DOI 10.1016/j.freeradbiomed.2009.11.005PMC PMC2818724

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Abstract

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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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
ORCID: Wang, Yong
Liu, Lingbo
Li, Hongliang
Meng, Aimin
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)
DOI: 10.1016/j.freeradbiomed.2009.11.005
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
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
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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Total body irradiation causes residual bone marrow injury by induction of persistent oxidative stress in murine hematopoietic stem cells

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