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 gamma-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 (C) 2010 Elsevier Inc All rights reserved