Immunological responses to hydrogel-aided induced pluripotent stem cell-derived dopaminergic progenitor transplants in immunodeficient versus cyclosporine immunosuppressed rats.

Abstract

The success of stem cell-derived brain repair for Parkinsons is limited by the variable survival and poor maturation of dopaminergic progenitors after transplantation into the Parkinsonian brain. One approach that has been developed to improve this is engraftment of the cells within a neurotrophin-enriched collagen hydrogel. Although this has been shown to improve progenitor survival and maturation in athymic nude rats, the same beneficial effects of the hydrogel were not seen in cyclosporine immunosuppressed rats. To determine the reasons for these differences, the aim of this study was to assess the local and systemic immune responses to progenitor transplantation in these two recipient groups. To do so, human induced pluripotent stem cell-derived dopaminergic progenitors were transplanted into 6-hydroxydopamine-lesioned striatum of athymic or cyclosporine immunosuppressed rats. The cells were transplanted either alone, with the neurotrophins GDNF and BDNF, in an unloaded collagen hydrogel, or in a neurotrophin-loaded collagen hydrogel. Post-mortem assessment included both graft site and blood analysis of immune cell populations. As expected, nude rats showed a pronounced innate immune cell response at the graft site but no T-cell recruitment or activation locally or systemically. In contrast, while the immunosuppressed rats also showed the expected innate immune cells response to the transplant, there was also infiltration of CD4+ and CD8+ T cells at the site of transplantation as well as circulating activated T-cells. Thus, this study suggests that the benefits of the hydrogel that were seen in the athymic nude rats did not manifest in the cyclosporine immunosuppressed rats due to incomplete immunosupression. This study shows the importance of careful optimisation of the immunosuppressive regime chosen before xenotransplantation experiments.