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 cause 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, neither the molecular mechanisms by which IR and/or chemotherapy induce HSC senescence have been clearly defined, nor has an effective treatment been developed to ameliorate the injury. Thus, they were investigated in the present study. The results from this study showed that exposure of mice to a sublethal dose 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-acetyl-cysteine (NAC) 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 likely attributed 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 (DPI) 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.

NADPH oxidase DUOX1 promotes long-term persistence of oxidative stress after an exposure to irradiation

“…A radiation-induced increase in ROS generation and/or an oxidative stress has been observed in vivo (21). Our results reveal that both DUOX1 and its maturation factor DUOXA1 are up-regulated several days after irradiation in human thyrocytes, supporting the role of DUOX1-based NADPH oxidase in a chronic oxidative stress.…”

Hematopoietic Stem Cell Injury Induced by Ionizing Radiation

“…Increased production of ROS in association with HSC defect has been observed in several other pathological conditions, such as deletion of Bmi1 (127, 136), MDM2 (1) and TSC1 (23), Fanconi anemia mutation (38), and aging (68). Similarly, we showed that exposure of mice to a sublethal dose of TBI induced a persistent increase in ROS production in HSCs (157). The induction of chronic oxidative stress was associated with sustained increases in oxidative DNA damage in HSCs, inhibition of HSC clonogenic function, and induction of HSC senescence (32, 90, 157).…”

NADPH Oxidase-generated Hydrogen Peroxide Induces DNA Damage in Mutant FLT3-expressing Leukemia Cells

“…Also, NOX4, localized in the perinuclear space was also the source of nuclear superoxide generation in hepatocytes (38). Interestingly, exposure of mice to ionizing radiation increased the expression of NOX4 in hematopoietic stem cells (10,39). The inhibition of NOX in the ionizing radiation-treated mice, attenuated the ROS and DNA damage associated with the ionizing radiation (40).…”