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

Georgia Panagiotakos,Rory Abrams,Viviane Tabar,Edward Greenberg,Philip Gutin,Amit Saxena,George Alshamy,Michelle Bradbury,Bill Chan,Mark Edgar,Schahram Akbarian

doi:10.1371/journal.pone.0000588

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.

Highlights

Radiation therapy is a powerful tool in the treatment of primary and metastatic cancers of the brain
Whole brain irradiation permanently decreases the number of proliferating cells in the subventricular zone (SVZ), the corpus callosum and the cortex
Sparing of the olfactory bulbs was confirmed by a double exposure X-ray of the skull prior to each radiation exposure (Fig. 1A)

Summary

Introduction

Radiation therapy is a powerful tool in the treatment of primary and metastatic cancers of the brain. While the pathogenesis is not fully understood, studies of brain irradiation in humans[4] and animals[5] suggest the loss of myelin sheaths with apparent preservation of axons. It is recognized that there are two major specialized zones of cell proliferation in the adult brain: the subventricular zone (SVZ) and the dentate gyrus These regions contain stem cell and precursor populations that self-renew and generate neurons and glia throughout life[8,9]. This 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

Methods

Results

Conclusion