Radiation Response of Neural Precursor Cells: Linking Cellular Sensitivity to Cell Cycle Checkpoints, Apoptosis and Oxidative Stress

Abstract

Therapeutic irradiation of the brain can cause a progressive cognitive dysfunction that may involve defects in neurogenesis. In an effort to understand the mechanisms underlying radiation-induced stem cell dysfunction, neural precursor cells isolated from the adult rat hippocampus were analyzed for acute (0-24 h) and chronic (3-33 days) changes in apoptosis and reactive oxygen species (ROS) after exposure to X rays. Irradiated neural precursor cells exhibited an acute dose-dependent apoptosis accompanied by an increase in ROS that persisted over a 3-4-week period. The radiation effects included the activation of cell cycle checkpoints that were associated with increased Trp53 phosphorylation and Trp53 and p21 (Cdkn1a) protein levels. In vivo, neural precursor cells within the hippocampal dentate subgranular zone exhibited significant sensitivity to radiation. Proliferating precursor cells and their progeny (i.e. immature neurons) exhibited dose-dependent reductions in cell number. These reductions were less severe in Trp53-null mice, possibly due to the disruption of apoptosis. These data suggest that the apoptotic and ROS responses may be tied to Trp53-dependent regulation of cell cycle control and stress-activated pathways. The temporal coincidence between in vitro and in vivo measurements of apoptosis suggests that oxidative stress may provide a mechanistic explanation for radiation-induced inhibition of neurogenesis in the development of cognitive impairment.

Ionizing radiation induces apoptosis and inhibits neuronal differentiation in rat neural stem cells via the c-Jun NH2-terminal kinase (JNK) pathway

“…Radiation-induced apoptosis in the central nervous system has been studied extensively in the animal model. Some recent studies revealed that radiation induced apoptosis in neural stem/progenitor cells (Peissner et al, Role of JNK in radiation effects on neural stem cells T Kanzawa et al 1999; Monje et al, 2002;Limoli et al, 2004). However, few studies reported the involvement of MAPKs in the process.…”

“…Recently, the hippocampus has been recognized as one of the regions where neural stem cells (NSCs) continue to proliferate and generate neurons throughout life. In the animal model of cranial irradiation, neural stem/precursor cells in the hippocampus undergo apoptosis, and neurogenesis is suppressed (Peissner et al, 1999;Madsen et al, 2003;Limoli et al, 2004). Monje et al(2002) studied the association between the radiation effects on NSCs and changes in the microenvironment.…”

Rescue of radiation-induced cognitive impairment through cranial transplantation of human embryonic stem cells

“…Ultimately, the success (or failure) of such approaches will depend on the functional engraftment of transplanted cells into the irradiated tissue bed. In the CNS, irradiation triggers a complex and multifactorial response involving persistent increases in oxidative species and inflammatory cytokines that actively participate in the remodeling of the irradiated microenvironment (42,43). The protracted nature of the CNS radiation response contributes to the inhibition of endogenous neurogenesis (21,44) and impairs the differentiation of neural precursor cells when transplanted into the irradiated brain (45).…”

Emerging Role of Neurocognitive Sparing Radiotherapy: Can it be the New Standard of Care?

“…Studies have shown that doses as low as even less than 10 Gy can cause neurocognitive dysfunction [22]. The central location of hippocampus makes it quite challenging to allow uniform dose delivery to the rest of the brain while avoiding the hippocampus.…”