Grafting of neural stem and progenitor cells to the hippocampus of young, irradiated mice causes gliosis and disrupts the granule cell layer

In pediatric hematology and oncology almost one-third of the cases are brain tumors and the incidence has increased over the past decades.1, 2, 3 Approximately 70% of pediatric brain tumor patients survive, and the survival rate has improved greatly in the past decades.4, 5 Despite improved techniques in neurosurgery and advances in chemotherapy, radiation therapy (RT) remains an essential treatment modality for malignant brain tumors, as well as for central nervous system (CNS) involvement of leukemia and lymphoma. However, RT is also one of the major causes of long-term complications seen in survivors of pediatric brain tumors. Cognitive impairments, secondary malignancies as well as perturbed growth and puberty are some of the so-called late effects seen after RT, and cognitive deficits have been shown to be more severe in younger children after RT.6, 7 Even low doses of ionizing radiation to the CNS are believed to cause cognitive impairment,8 and the impairments increase over time after RT. Hence, ameliorating the late effects of radiotherapy would greatly improve the quality of life of the increasing number of cancer survivors, particularly in children where the remaining life expectancy is long. The injury caused by irradiation (IR) affects many brain regions and cell types, but the underlying pathogenesis is not well understood. Neurogenesis occurs throughout life in the subventricular zone and in the dentate gyrus (DG) of the hippocampus, making these regions harboring proliferating cells particularly susceptible to IR.9, 10 It has been suggested that injury to neural stem and progenitor cells (NSPCs) in the hippocampus contributes to some of the late effects seen after IR,11, 12, 13, 14, 15 and IR-induced depletion of neural stem cells appears to be long-lasting, if not permanent, even after a single, moderate dose of IR.16, 17 Very few potential interventions after RT have been investigated, but memory training was shown to improve the attention and memory performance of children treated for medulloblastoma.18 Interestingly, voluntary physical exercise was shown to increase the number of stem cells and the rate of neurogenesis after IR of the young mouse brain, and, furthermore, at least partly normalize the IR-induced behavior changes.13 Grafting of human embryonic stem cells into the hippocampus of irradiated adult immune-deficient rats improved their performance in a memory task.19 Grafting NSPCs into the hippocampus may be a promising therapy after IR also at young age. The host tissue properties can change dramatically after IR. We have shown that IR elicits a transient inflammatory reaction in the immature brain,20, 21 which is different in nature from the more long-lasting inflammation seen after IR to the adult brain.10, 22 In the adult rat brain, it has been shown that the inflammatory reaction to IR caused the remaining neural precursors to adopt glial fates, and transplants of non-irradiated neural precursor cells failed to differentiate into neurons in the irradiated hippocampus caused NSPCs to adopt a glial phenotype instead of a neuronal one to a higher extent.10 The aim of this study was to explore the effects of age and interval between IR and grafting on survival and differentiation to investigate the optimal time-point for transplantation therapy after IR.