Motor recovery and persistent inflammation after transplantation of human dopaminergic cells from pluripotent stem cells in animal models for Parkinson´s Disease

LEAL, M. CELESTE; PENG, JUN; QIUYUE LIU; WENKER, SHIRLEY; FARÍAS, ISABEL; FERRARI, CARINA; DEPINO, AMAICHA; NUÑEZ, MYRIAM; FERNICOLA, MARCELA; RADICE, PABLO; CAVALIERE CANDEDO, VERÓNICA; ZENG, XIANMIN; PITOSSI, FERNANDO

Vancouver

Congreso; 12th Annual Meeting International Society Stem Cell Research (ISSCR); 2014

Parkinson ´s Disease (PD) is a neurodegenerative disorder mainly characterized by the degeneration of dopaminergic neurons of the substantia nigra pars compacta (SN), leading to a dysfunctional nigro-striatal pathway. Transplantation of dopamine-producing cells into the striatum has already shown its effectiveness in animal models and clinical trials, although undesired complications in a number of cases and the lack of Good Manufacture Practice (GMP)-grade cell preparation precludes its wide application in the clinic. Another major caveat of this approach is the low level of cell survival after transplantation We sought to test the effects of the striatal transplantation of dopaminergic neurons derived from human embryonic stem cells using a GMP-compatible process into rat models of Parkinson ´s Disease (PD). Adult rats were denervated by the inoculation of 6-OHDA, tested for motor asymmetry by the cylinder test and transplanted with 8 x 105 dopaminergic neurons or control cells into the striatum. Control cells were human pluripotent stem cells subjected to a similar differentiation protocol as the dopaminergic cells, but harvested 4 days before they start producing dopamine. Animals were immunosuppressed with cyclosporine A one day before transplantation and throughout the experiment. Pharmacological and non-pharmacological tests showed a clear improvement in motor behavior of animals transplanted with dopaminergic cells but not the control cells 12-13 weeks after transplantation. Persistent microglial activation at the site of transplantation was observed by MHC-II, ED-1 and GSA staining 90 days post-transplantation in dopaminergic- and control cells-treated animals. Similar experiments are being conducted in an inflammation-based animal model of PD. We conclude that the transplant of this GMP-compatible preparation of human dopaminergic neurons provides a robust motor recovery in the animals tested. In addition, the chronic inflammation observed at the site of transplantation opens up the possibility of increasing neuronal survival and differentiation by immunomodulaton.