Long-Term Impact of Radiation on the Stem Cell and Oligodendrocyte Precursors in the Brain

Abstract

BackgroundThe cellular basis of long term radiation damage in the brain is not fully understood.Methods and FindingsWe administered a dose of 25Gy to adult rat brains while shielding the olfactory bulbs. Quantitative analyses were serially performed on different brain regions over 15 months. Our data reveal an immediate and permanent suppression of SVZ proliferation and neurogenesis. The olfactory bulb demonstrates a transient but remarkable SVZ-independent ability for compensation and maintenance of the calretinin interneuron population. The oligodendrocyte compartment exhibits a complex pattern of limited proliferation of NG2 progenitors but steady loss of the oligodendroglial antigen O4. As of nine months post radiation, diffuse demyelination starts in all irradiated brains. Counts of capillary segments and length demonstrate significant loss one day post radiation but swift and persistent recovery of the vasculature up to 15 months post XRT. MRI imaging confirms loss of volume of the corpus callosum and early signs of demyelination at 12 months. Ultrastructural analysis demonstrates progressive degradation of myelin sheaths with axonal preservation. Areas of focal necrosis appear beyond 15 months and are preceded by widespread demyelination. Human white matter specimens obtained post-radiation confirm early loss of oligodendrocyte progenitors and delayed onset of myelin sheath fragmentation with preserved capillaries.ConclusionsThis study demonstrates that long term radiation injury is associated with irreversible damage to the neural stem cell compartment in the rodent SVZ and loss of oligodendrocyte precursor cells in both rodent and human brain. Delayed onset demyelination precedes focal necrosis and is likely due to the loss of oligodendrocyte precursors and the inability of the stem cell compartment to compensate for this loss.

Radiation-induced brain injury: low-hanging fruit for neuroregeneration

“…As such, radiation results in a pervasive pattern of OPC loss and progressive demyelination that has been well characterized in rodents and humans. 65 Given the particular importance of white matter in cognitive tasks of working memory and executive function, diffuse white matter degeneration is a major contributor to radiation-induced cognitive impairment. Although this review focuses on the effects of radiation on oligodendrocyte progenitor cells, it should be noted that OPC function is additionally impaired by certain chemotherapeutic agents, 26,30 the combinatorial effects of which further exacerbate white matter atrophy following treatment of brain tumors.…”

Irradiation to the Young Mouse Brain Caused Long-Term, Progressive Depletion of Neurogenesis but did not Disrupt the Neurovascular Niche

“…Considerably fewer studies have investigated the effects of irradiation on the young, developing brain and very little is known about how microvessels in the hippocampus respond to this type of insult. [17][18][19] Therefore, the primary aim of this study was to investigate how microvessels in the hippocampus were affected by irradiation to the young mouse brain, by quantifying blood vessel parameters at different time points after irradiation. We also sought to investigate the role of the neurovascular niche in the support and survival of neural stem/progenitor cells.…”

Extracellular superoxide dismutase is important for hippocampal neurogenesis and preservation of cognitive functions after irradiation

“…Ionizing irradiation not only results in the acute generation of short-lived ROS, it also results in a persistent state of oxidative stress that extends up to several months or even years after irradiation (12,13). Accordingly, animal and cell models with altered antioxidant capacities have been used to investigate the biochemical pathways involved in radiation-induced tissue and cell injuries, and experimental antioxidant-based therapies have been designed to protect normal tissues during radiation treatments (14).…”