Conditionally immortal neuroepithelial stem cell grafts restore spatial learning in rats with lesions at the source of cholinergic forebrain projections

Purpose: Loss of cholinergic projections from the basal forebrain (BF) to t he cortex and from the medial septal area (MSA) to the hippocampus is a rel iable correlate of cognitive deficits in aging and Alzheimer's disease (AD) . We assessed the capacity of grafts of the conditionally immortal MHP36 cl onal stem cell line to improve spatial learning in rats showing profound de ficits after lesions to these projections. Methods: Rats were lesioned by infusions of S-AMPA unilaterally into BF or bilaterally into both BF and MSA. MHP36 cells were implanted ipsilaterally in cortex or basal forebrain two weeks after unilateral BF lesions, and in cortex and hippocampus bilaterally six months after bilateral BF-MSA lesion s. Intact and lesion-only controls received vehicle. Six weeks later rats w ere assessed in spatial learning and memory tasks in the water maze, and th en perfused for identification of grafted cells by beta -galactosidase immu nohistochemistry. Results: Lesioned rats with MHP36 grafts, whether implanted two weeks or si x months after lesioning, learned to find a submerged platform in the water maze as rapidly as intact controls, and showed a strong preference for the platform quadrant on probe trials, whereas lesioned controls were impaired in all measures. Grafted cells of both neuronal and glial morphologies, mi grated away from cortical implantation sites in BF lesioned rats to the str iatum, thalamus and basal forebrain lesion area. Cells implanted in basal f orebrain showed a similar distribution. In rats with bilateral BF-MSA lesio ns, grafts implanted in the hippocampus migrated widely through all layers but cortical grafts largely escaped up the needle tract into the meninges. Conclusions: Although MHP36 grafts were functionally effective in both lesi on models, the site and age of lesions and site of implantation influenced the pattern of engraftment. This flexibility encourages the development of conditionally immortal human stem cell lines with similar capacities for fu nctional repair of variable neuronal degeneration in AD or aging.