Consequences of ionizing radiation-induced damage in human neural stem cells.
Cranial irradiation remains a frontline treatment for brain cancer, but also leads to normal tissue damage. Although low-dose irradiation (≤10 Gy) causes minimal histopathologic change, it can elicit variable degrees of cognitive dysfunction that are associated with the depletion of neural stem cells. To decipher the mechanisms underlying radiation-induced stem cell dysfunction, human neural stem cells (hNSCs) subjected to clinically relevant irradiation (0-5 Gy) were analyzed for survival parameters, cell-cycle alterations, DNA damage and repair, and oxidative stress. hNSCs showed a marked sensitivity to low-dose irradiation that was in part due to elevated apoptosis and the inhibition of cell-cycle progression that manifested as a G2/M checkpoint delay. Efficient removal of DNA double-strand breaks was indicated by the disappearance of γ-H2AX nuclear foci. A dose-responsive and persistent increase in oxidative and nitrosative stress was found in irradiated hNSCs, possibly the result of a higher metabolic activity in the fraction of surviving cells. These data highlight the marked sensitivity of hNSCs to low-dose irradiation and suggest that long-lasting perturbations in the CNS microenvironment due to radiation-induced oxidative stress can compromise the functionality of neural stem cells.
Acharya
Munjal M
MM
Department of Radiation Oncology, University of California at Irvine, Irvine, CA 92697-2695, USA.
Lan
Mary L
ML
Kan
Vickie H
VH
Patel
Neal H
NH
Giedzinski
Erich
E
Tseng
Bertrand P
BP
Limoli
Charles L
CL
D017209:Apoptosis / Q000528:radiation effects; D002453:Cell Cycle / Q000528:radiation effects; D002454:Cell Differentiation / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D002478:Cells, Cultured; D004249:DNA Damage / Q000528:radiation effects; D004260:DNA Repair / Q000528:radiation effects; D005720:Gamma Rays; D006657:Histones / Q000378:metabolism; D006801:Humans; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D009569:Nitric Oxide / Q000378:metabolism / Q000528:radiation effects; D018384:Oxidative Stress / Q000528:radiation effects; D011832:Radiation Injuries / Q000473:pathology*
C468783:H2AX protein, human; D006657:Histones; D009569:Nitric Oxide