Human Neural Stem Cell Transplantation Ameliorates Radiation-Induced Cognitive Dysfunction

Abstract

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.

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

“…The initial acquisition of the conditioned freezing response was not impacted in any of the cohorts (similar posttraining), nor was amygdala function (similar cue test) (20). These data indicate that radiation-induced deficits in hippocampal function could be ameliorated using MV and were functionally equivalent to hNSCs used under similar conditions in many of our past studies (4,8).…”

“…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).…”

“…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). These studies have shown that our stem cell-based approaches improve the functional plasticity of the host brain through a variety of mechanisms including (i) the suppression of neuroinflammation (5), (ii) the addition of new cells to active hippocampal circuits (4), and (iii) a long-term trophic support mechanism that facilitates the expression of activity-regulated cytoskeletonassociated protein that functions in multiple ways as a molecular determinant of memory (7).…”

“…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). These studies have shown that our stem cell-based approaches improve the functional plasticity of the host brain through a variety of mechanisms including (i) the suppression of neuroinflammation (5), (ii) the addition of new cells to active hippocampal circuits (4), and (iii) a long-term trophic support mechanism that facilitates the expression of activity-regulated cytoskeletonassociated protein that functions in multiple ways as a molecular determinant of memory (7). Moreover, using a distinctly different injury paradigm, stem cell grafting preserved host neuronal morphology in rats that otherwise experienced significant disruptions to dendritic complexity following a chronic chemotherapy regimen (8).…”

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).…”