Co-Grafts of Fetal Ventral Mesencephalon and Fibroblasts Expressing Sonic Hedgehog: Effect on Survival and Function of Dopamine Grafts

Abstract

Fibroblasts derived from the Rat2 parental cell line were genetically modified to express the cell-associated form of Sonic hedgehog (Shh) and then co-grafted along with E14 fetal ventral mesencephalon (VM) tissue into the denervated striatum of F344 rats; fetal VM grafts alone or co-grafts using the nonexpressing Rat2 fibroblasts served as controls. Seven weeks after grafting, co-grafts of fetal VM and fibroblasts expressing Shh (Rat2/Shh) contained significantly more tyrosine hydroxylase-positive (TH+) neurons than either the fetal VM grafts or co-grafts of fetal VM plus nonexpressing fibroblasts (Rat2). Despite a significantly higher yield of grafted TH+ neurons in the fetal VM + Rat2/Shh co-grafts than in either of the other two control groups, amphetamine-induced rotational behavior scores were not significantly different between any of the three treatment groups. The number of TH+ neurons in the Rat2 (nonexpressing) co-grafts was significantly lower than the other two treatment groups. The results from this study suggest that fibroblasts expressing Shh may improve the number of co-grafted dopamine neurons, but do not improve the functional capacity of the graft in terms of improving amphetamine-induced rotational behavior.