Long-term impact of radiation on the stem cell and oligodendrocyte precursors in the brain.
BACKGROUND
The cellular basis of long term radiation damage in the brain is not fully understood.


RESULTS
We 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.


CONCLUSIONS
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.
Panagiotakos
Georgia
G
Department of Neurosurgery, Sloan-Kettering Institute for Cancer Research, New York, New York, United States of America.
Alshamy
George
G
Chan
Bill
B
Abrams
Rory
R
Greenberg
Edward
E
Saxena
Amit
A
Bradbury
Michelle
M
Edgar
Mark
M
Gutin
Philip
P
Tabar
Viviane
V
D000818:Animals; D001921:Brain / Q000528:radiation effects*; D064032:Calbindin 2; D002455:Cell Division / Q000528:radiation effects; D002540:Cerebral Cortex / Q000528:radiation effects; D002552:Cerebral Ventricles / Q000502:physiology / Q000528:radiation effects; D003337:Corpus Callosum / Q000033:anatomy & histology / Q000528:radiation effects; D005260:Female; D006801:Humans; D007395:Interneurons / Q000502:physiology / Q000528:radiation effects; D008279:Magnetic Resonance Imaging; D009186:Myelin Sheath / Q000473:pathology / Q000528:radiation effects; D009336:Necrosis; D009830:Olfactory Bulb / Q000473:pathology / Q000528:radiation effects; D009836:Oligodendroglia / Q000528:radiation effects*; D011878:Radiotherapy / Q000009:adverse effects / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D064030:S100 Calcium Binding Protein G / Q000378:metabolism / Q000528:radiation effects; D013234:Stem Cells / Q000528:radiation effects*
C576764:CALB2 protein, human; C576512:Calb2 protein, rat; D064032:Calbindin 2; D064030:S100 Calcium Binding Protein G