Rescue of radiation-induced cognitive impairment through cranial transplantation of human embryonic stem cells

Abstract

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.cognition ͉ stem cells ͉ radiotherapy

Long-term survival of exogenous embryonic stem cells in adult bone marrow

“…Recently, transplanting human ESCs into the hippocampus of athymic nude rats has been shown to improve cognitive impairment caused by irradiation. The transplanted cells can migrate to the subgranular zone and exhibit signs of neuron morphology within the neurogenic niche with no observed overt adverse cognitive sequelae or intracranial teratogenesis [10]. In contrast, our study detected teratomas in about 30% of irradiated hosts and 7.5% of unirradiated hosts.…”

Cranial irradiation compromises neuronal architecture in the hippocampus

“…Past data in the same mouse background (i.e., C57Bl6) has found irradiation to elicit cognitive decrements, albeit at longer postirradiation intervals (9,10), and data from us and others using different strains of rat have shown irradiation to elicit hippocampal deficits in learning and memory (8,40,41). Recent data from us has also shown that lowdose irradiation of the same transgenic mouse strain with charged particles elicits decrements in cognition using a novel object recognition test (42).…”

“…Radiation Exposure. Mice 2-mo of age were anesthetized and exposed to cranial γ-irradiation (1 or 10 Gy) using a 137 Cs irradiator at a dose rate of 2.07 Gy/min, as previously described (8).…”

“…Based on experimental data in rodent models (8)(9)(10), these doses are likely to far exceed those typically required for the onset of radiationinduced cognitive dysfunction, which can manifest at much lower total doses (i.e., ≤10 Gy) than those used clinically (6,11). More radiosensitive populations of neural stem and progenitor cells do exist in the neurogenic regions of the brain, and radiation-induced depletion of these cells in the hippocampal dentate gyrus has been linked to spatial-temporal learning and memory deficits (9,10,12).…”

Cranial grafting of stem cell-derived microvesicles improves cognition and reduces neuropathology in the irradiated brain

“…Despite the recognition and prevalence of these adverse side effects, relatively few, if any, long-term satisfactory solutions exist for this unmet medical need. Past work from our laboratory has optimized transplantation parameters and established many of the long-term benefits of human stem cell-based therapies for the treatment of radiationinduced cognitive dysfunction (3)(4)(5). Cranially grafted stem cells have been shown to impart persistent improvements in behavioral performance in irradiated rats over extended postirradiation intervals (1-8 mo) using short-and long-term cognitive testing paradigms (4,6,7).…”