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In JoVE (1)
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Articles by Mary L. Lan in JoVE
JoVE Clinical and Translational Medicine
زرع الخلايا الجذعية استراتيجيات من أجل استعادة الضعف المعرفي التي تحدثها العلاج الإشعاعي القحف
Department of Radiation Oncology, University of California Irvine
المرضى الخضوع لورم في المخ بشكل روتيني بالأشعة في الجمجمة ، وبينما مفيدة ، غالبا ما يؤدي هذا الخلل في العلاج المعرفي الموهنة هذه المشكلة الخطيرة التي لم تحل في الوقت الحاضر قد لا تلجأ السريرية ، ودفع جهودنا الرامية إلى وضع علاجات الخلايا الجذعية استنادا لاسترداد التناقصات المعرفية الناجمة عن الإشعاع.
Other articles by Mary L. Lan on PubMed
Rescue of Radiation-induced Cognitive Impairment Through Cranial Transplantation of Human Embryonic Stem Cells
Cranial irradiation remains a frontline treatment for the control of tumor growth, and individuals surviving such treatments often manifest various degrees of cognitive dysfunction. Radiation-induced depletion of stem/precursor cell pools in the brain, particularly those residing in the neurogenic region of the hippocampus, is believed, in part, to be responsible for these often-unavoidable cognitive deficits. To explore the possibility of ameliorating radiation-induced cognitive impairment, athymic nude rats subjected to head only irradiation (10 Gy) were transplanted 2 days afterward with human embryonic stem cells (hESC) into the hippocampal formation and analyzed for stem cell survival, differentiation, and cognitive function. Animals receiving hESC transplantation exhibited superior performance on a hippocampal-dependent cognitive task 4 months postirradiation, compared to their irradiated surgical counterparts that did not receive hESCs. Significant stem cell survival was found at 1 and 4 months postirradiation, and transplanted cells showed robust migration to the subgranular zone throughout the dentate gyrus, exhibiting signs of neuron morphology within this neurogenic niche. These results demonstrate the capability to ameliorate radiation-induced normal tissue injury using hESCs, and suggest that such strategies may provide useful interventions for reducing the adverse effects of irradiation on cognition.
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.
Human Neural Stem Cell Transplantation Ameliorates Radiation-induced Cognitive Dysfunction
Cranial radiotherapy induces progressive and debilitating declines in cognition that may, in part, be caused by the depletion of neural stem cells. The potential of using stem cell replacement as a strategy to combat radiation-induced cognitive decline was addressed by irradiating athymic nude rats followed 2 days later by intrahippocampal transplantation with human neural stem cells (hNSC). Measures of cognitive performance, hNSC survival, and phenotypic fate were assessed at 1 and 4 months after irradiation. Irradiated animals engrafted with hNSCs showed significantly less decline in cognitive function than irradiated, sham-engrafted animals and acted indistinguishably from unirradiated controls. Unbiased stereology revealed that 23% and 12% of the engrafted cells survived 1 and 4 months after transplantation, respectively. Engrafted cells migrated extensively, differentiated along glial and neuronal lineages, and expressed the activity-regulated cytoskeleton-associated protein (Arc), suggesting their capability to functionally integrate into the hippocampus. These data show that hNSCs afford a promising strategy for functionally restoring cognition in irradiated animals.
