Cellular Repair in the Parkinsonian Nonhuman Primate Brain

Abstract

Parkinson disease (PD) is a neurodegenerative disorder that provides a useful model for testing cell replacement strategies to rejuvenate the affected dopaminergic neural systems, which have been destroyed by aging and the disease. We first showed that grafts of fetal dopaminergic neurons can reverse parkinsonian motor deficits induced by the toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), validating the feasibility of cellular repair in a primate nervous system. Subsequent clinical trials in Parkinson patients showed encouraging results, including long-term improvement of neurological signs and reduction of medications in some patients. However, many experienced little therapeutic benefit, and some recipients experienced dyskinesias, suggesting a lack of regulated control of the grafts. We have since attempted to improve cell replacements by placing grafts in their correct anatomical location in the substantia nigra and using strategies such as co-grafting fetal striatal tissue or growth factors into the physiologic striatal targets. Moreover, the use of fetal cells depends on a variable supply of donor material, making it difficult to standardize cell quality and quantity. Therefore, we have also explored possibilities of using human neural stem cells (hNSCs) to ameliorate parkinsonism in nonhuman primates with encouraging results. hNSCs implanted into the striatum showed a remarkable migratory ability and were found in the substantia nigra, where a small number appeared to differentiate into dopamine neurons. The majority became growth factor-producing glia that could provide beneficial effects on host dopamine neurons. Studies to determine the optimum stage of differentiation from embryonic stem cells and to derive useful cells from somatic cell sources are in progress.

Induced Pluripotent Stem Cell-Derived Neural Cells Survive and Mature in the Nonhuman Primate Brain

“…Cell therapy is one potential future application of stem cells, especially of iPSCs, given the possibility of autologous transplantation (Brundin et al, 2010; Redmond et al, 2010; Deleidi et al, 2011). Although teratomas are rejected by syngenic mice, stem cell therapy will unlikely employ iPSCs themselves.…”

Large animal models for stem cell therapy

“…A significant advantage of the use of large, long-lived animals is the ability to have a longer observation time for possible side effects as well as therapeutic benefits. The use of non-human primates also permitted the evaluation of the potential for reconstruction of the full dopaminergic pathway by co-grafting fetal tissue or growth factors into the striatum and substantia nigra at distances similar to those in the human brain [40]. Despite these advances in animal models, human trials so far have shown very modest and variable improvement, indicating that further optimization of techniques is required to improve efficacy before clinical use.…”

Defining and designing polymers and hydrogels for neural tissue engineering

“…That there have been some successful outcomes provides proof of concept that replacing lost neural cells through neural grafting or implantation can be a viable treatment option. However, the large scale loss of grafted cells in the days following implantation is most likely the biggest contributor to their variable success (Barker et al, 1996; Meyer et al, 1998; Bjugstad et al, 2008; Yu et al, 2009; Redmond et al, 2010). To improve the outcomes of cell implantation into the central nervous system (CNS), there needs to be some method of protecting the neural grafts from the host response to the implant procedure and for guiding graft growth and integration.…”