title: Total body irradiation causes residual bone marrow injury by induction of persistent oxidative stress in murine hematopoietic stem cells.
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.
authors.affiliation: Department of Pathology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Lingbo
authors.initials: L
authors.lastname: Liu
authors.forename: Senthil K
authors.initials: SK
authors.lastname: Pazhanisamy
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
authors.forename: Aimin
authors.initials: A
authors.lastname: Meng
authors.forename: Daohong
authors.initials: D
authors.lastname: Zhou
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage; D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000096:biosynthesis* / Q000235:genetics; D009861:Onium Compounds / Q000494:pharmacology; D018384:Oxidative Stress; D011833:Radiation Injuries, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D023001:Transplantation Tolerance / Q000187:drug effects; D014916:Whole-Body Irradiation
chemical_list: D009861:Onium Compounds; D017382:Reactive Oxygen Species; C007517:diphenyleneiodonium; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; D000111:Acetylcysteine