Nerve Growth Factor Delivery and Cell Aggregation Enhance Choline Acetyltransferase Activity after Neural Transplantation

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Abstract
Fetal cell transplantation may improve the treatment of neurodegenerative diseases, but the optimal conditions for cell transplantation have not yet been defined. In this study, we examined the influence of preaggregation of dissociated donor cells and delivery of an appropriate growth factor on cell survival following transplantation. Cell aggregates were produced by culturing dissociated cells in conventional rotation culture or in a rotating-wall bioreactor. Suspensions of dissociated septal cells from E16 embryos, or suspensions containing small aggregates (µm) of these cells, were transplanted into the brains of adult rats. In some cases, transplanted cells were supplied with nerve growth factor (NGF), a neurotrophin known to promote the survival and function of septal cholinergic cells; NGF was delivered to the transplant site by controlled-release polymers or genetically engineered fibroblasts. Cell function after transplantation was determined by measuring the increase in choline acetyltransferase (ChAT) activity in brain tissue sections encompassing the transplant site. Aggregation of cells prior to transplantation enhanced ChAT activity; at 2 months posttransplantation, ChAT levels were always slightly higher in animals receiving aggregated donor cells than in those receiving single cell suspensions. NGF delivery also enhanced ChAT activity; controlled release polymers produced the largest effect 2 weeks posttransplantation, while NGF-secreting fibroblasts produced significant enhancement at 2 months posttransplantation. These different patterns of enhanced ChAT activity appear to be due to differences in the rate of NGF delivery provided by these two techniques. These studies indicate that cell aggregation and NGF delivery systems may provide important new tools for the enhancement of cell function after transplantation.