Modulating Wnt signaling to improve cell replacement therapy for Parkinson's disease

Clinical trials have demonstrated the capacity for dopamine neurons, transplanted ectopically into the striatum, to structurally integrate, restore dopamine transmission, and induce long-term functional benefits for Parkinson's disease (PD) patients. Despite this proof of principle, a number of limitations have hindered the development of cell replacement therapy over the past 20 years, particularly tissue availability, graft survival, and adequate reinnervation of the host brain. With a greater understanding of failure in prior clinical trials, increased knowledge of midbrain dopamine development (now including Wnts), and the development of pluripotent stem cell technologies, we are better equipped than ever to re-address a number of these challenges. This review summarizes the trials, tribulations, and progress in cell replacement therapy for PD. We discuss the prospects of modulating canonical and non-canonical Wnt signaling to improve cell therapy based upon their roles in dopamine neural development and the adult brain. This will include the potential of Wnts to (i) expand fetally derived tissue in vitro and following transplantation, (ii) promote the differentiation of pluripotent stem cells, (iii) increase graft integration and restoration of neural circuitry, and finally (iv) enhance graft survival.