Although human induced pluripotent stem cell (iPSC)-derived cell replacement for Parkinson’s disease has considerable reparative potential, its full therapeutic benefit is limited by poor graft survival and dopaminergic maturation. Injectable biomaterial scaffolds, such as collagen hydrogels, have the potential to address these issues via a plethora of supportive benefits to aid survival and differentiation. Professor Dowd’s recent research has demonstrated that neurotrophin-enriched collagen hydrogels can dramatically improve the survival (x 8-fold) and maturation (x 13-fold) of human iPSC-derived dopaminergic grafts in Parkinsonian rats.
However, curiously, this beneficial effect was only seen in immunocompromised (nude) rats and not in immunosuppressed rats (in which cyclosporine was started one day before transplants). Given that most Parkinson’s patients receiving cell transplantation therapy in the future will likely receive donor-derived transplants with immunosuppression, extending the beneficial effect of the hydrogel to immunosuppressed rats is critical. Therefore, the aim of this study is to determine if a modified immunosuppression regime (cyclosporine starting seven days before transplants) will allow the beneficial effect of the biomaterial to manifest. For this project, human iPSC-derived dopaminergic neurons will be transplanted into the Parkinsonian (6-hydroxydopamine-lesioned) striatum either alone, with the neurotrophins GDNF and BDNF, in an unloaded collagen hydrogel, or in a neurotrophin-loaded collagen hydrogel. During my project, I will work on the post-mortem tissue from these animals to quantify graft survival and maturation using immunohistochemistry for human nuclei (HuNu) and the dopaminergic marker tyrosine hydroxylase, respectively.