Enhanced cell survival in fetal hippocampal suspension transplants grafted to adult rat hippocampus following kainate lesions: a three-dimensional graft reconstruction study.
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abstract
The success of fetal neural transplantation in alleviating neurological dysfunction depends significantly on the degree of graft cellular survival and dispersion within the host. We hypothesize that various lesion-induced host factors, such as trophic support and denervation, enhance these graft factors differentially following unilateral intracerebroventricular kainic acid lesions. We have performed quantitative graft reconstructions of embryonic day 19 fetal hippocampal cells transplanted at different post-lesion delays (four, 11, 26 and 60 days) into adult hippocampus. We have used a permanent graft prelabel (5'-bromodeoxyuridine) which allows unambiguous identification of graft cell location in the host. Cellular integration of grafted cells was rigorously assessed by calculating both absolute cell survival (cells recovered/cells injected) and quantitative cell dispersion from the graft injection site. Graft cell survival and graft volume were dramatically enhanced in transplants performed ipsilateral to the kainic acid lesion, to a maximum of 77% cell recovery at a post-lesion graft delay of four days. Cell survival decreased over time after the lesion to the level of the contralateral grafts by 60 days post-lesion (33% cell survival), though cell survival on either side remained significantly greater than grafts into normal hosts (18% survival). The time-course of post-lesion enhanced survival (four to 26 days) in hippocampus ipsilateral to the lesion strongly correlated with reported peak neurotrophic activity (four to 30 days). Graft cell dispersion was limited in this model, averaging less than 500-microns-cell movement; there were no differences compared to transplants grafted into normal hippocampus. Timm's staining demonstrated host mossy fiber innervation of transplants to be denser ipsilateral to the kainic acid lesion, resulting in a partial decrease in dentate supragranular sprouting near appropriate grafts placed at early post-lesion time points. These results suggest that lesion-induced trophic support and denervation lead to improved graft cell survival but not graft cell dispersion. The improved survival of grafts transplanted into hippocampus contralateral to the lesion, compared to transplants in normal hippocampus, suggests that denervation alone exerts a significant effect on graft cell survival. However, this denervation effect on graft cell survival is significantly less than the combination of both enhanced neurotrophic factors and denervation observed ipsilateral to the lesion.
