Simultaneous Transplantation of Fetal Ventral Mesencephalic Tissue and Encapsulated Genetically Modified Cells Releasing GDNF in a Hemi-Parkinsonian Rat Model of Parkinson’s Disease

Transplantation of fetal ventral mesencephalic (VM) neurons for Parkinson's disease (PD) is limited by poor survival and suboptimal integration of grafted tissue into the host brain. In a 6-OHDA rat model of PD we investigated the feasibility of simultaneous transplantation of rat fetal VM tissue and polymer-encapsulated C2C12 myoblasts genetically modified to produce glial cell line-derived neurotrophic factor or mocktransfected myoblasts on graft function. Amphetamine-induced rotations were assessed prior and 2, 4, 6 and 9 weeks post-transplantation. We found that rats grafted with VM transplants and GDNF-capsules showed a significant functional recovery already 4 weeks after implantation. In contrast, rats from the VM transplant and mock-capsule group did not improve at any time point analyzed. Moreover, we detected a significantly higher number of tyrosine hydroxylase-immunoreactive (TH-ir) cells per graft (2 fold), a tendency for a larger graft volume and an overall higher TH-ir fiber outgrowth into the host brain (1.7 fold) in the group with VM transplants and GDNF-capsules as compared to the VM transplant and mock-capsule group. Most prominent was the TH-ir fiber outgrowth towards the capsule (9 fold). Grafting of GDNF pre-treated VM transplants in combination with the implantation of GDNF-capsules resulted in a tendency for a higher TH-ir fiber outgrowth into the host brain (1.7 fold) as compared to the group transplanted with untreated VM transplants and GDNF-capsules. No differences between groups were observed for the number of surviving TH-ir neurons or graft volume. In conclusion, our findings demonstrate that simultaneous transplantation of fetal VM tissue and encapsulated GDNF-releasing cells is feasible and support the graft survival and function. Pre-treatment of donor tissue with GDNF may offer a way to further improve cell transplantation approaches for PD.