Redox regulation of stem cell compartments: The convergence of radiation-induced normal tissue damage and oxidative stress

Abstract

The redox environment impacts normal stem cell niches throughout the body. Hematopoietic, muscle, and neural stem cell compartments respond to changes in reactive oxygen (ROS) and nitrogen (RNS) species by triggering signaling networks that impact cellular proliferation, survival, and differentiation. Work from many labs including our own has found that irradiation can trigger acute and chronic increases in oxidative stress. Low dose and/or protracted dose rates can elicit radioadaptive changes that have beneficial effects on proliferation and survival while influencing the development lineage-specific cell fates. Higher doses and dose rates have been found to impede the regeneration of irradiated tissues, through the depletion and/or damage of endogenous stem cell pools, and by promoting the onset and persistence of secondary reactive processes involving oxidative stress and inflammatory cytokines. Increasing evidence suggests that these important stem cell pools are differentially protected from DNA damaging agents compared to their immediate progeny (i.e., precursor/progenitor cells) due to enhanced DNA repair, antioxidant status, and reduced cell cycle activity. Thus, many of the adverse effects of irradiation on normal tissue are the consequence of damage to the rapidly expanding pool of precursor cells derived from asymmetric cell division. Irradiation of the bone marrow impairs the health of bone by promoting osteoclastogenesis (osteoclast-mediated bone resorption) and inhibiting osteoblastogenesis (osteoblast-mediated bone formation), with the net effect of reducing bone mass and structural integrity. Irradiation of the skeletal musculature impairs myogenesis (formation of muscle tissue) by damaging satellite cells (i.e., muscle stem cells) and reducing proproliferative levels of nitric oxide. In the brain, irradiation depletes neural stem and precursor cells and leads to persistent increases in ROS/RNS and inflammatory cytokines that inhibit neurogenesis (formation of new neurons and glia) and adversely impact cognition. In each of these foregoing cases, interventions targeted to reduce specific reactive species can attenuate the adverse effects of radiation exposure and point to the importance of understanding the interplay between endogenous stem cell niches and the microenvironmental redox state.