Primate adult brain cell autotransplantation produces behavioral and biological recovery in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐induced parkinsonian St. Kitts monkeys

Abstract

The potential for "replacement cells" to restore function in Parkinson's disease has been widely reported over the past 3 decades, rejuvenating the central nervous system rather than just relieving symptoms. Most such experiments have used fetal or embryonic sources that may induce immunological rejection and generate ethical concerns. Autologous sources, in which the cells to be implanted are derived from recipients' own cells after reprogramming to stem cells, direct genetic modifications, or epigenetic modifications in culture, could eliminate many of these problems. In a previous study on autologous brain cell transplantation, we demonstrated that adult monkey brain cells, obtained from cortical biopsies and kept in culture for 7 weeks, exhibited potential as a method of brain repair after low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) caused dopaminergic cell death. The present study exposed monkeys to higher MPTP doses to produce significant parkinsonism and behavioral impairments. Cerebral cortical cells were biopsied from the animals, held in culture for 7 weeks to create an autologous neural cell "ecosystem" and reimplanted bilaterally into the striatum of the same six donor monkeys. These cells expressed neuroectodermal and progenitor markers such as nestin, doublecortin, GFAP, neurofilament, and vimentin. Five to six months after reimplantation, histological analysis with the dye PKH67 and unbiased stereology showed that reimplanted cells survived, migrated bilaterally throughout the striatum, and seemed to exert a neurorestorative effect. More tyrosine hydroxylase-immunoreactive neurons and significant behavioral improvement followed reimplantation of cultured autologous neural cells as a result of unknown trophic factors released by the grafts.

Enhancement of Striatal Dopaminergic Function Following Autologous Neural Cell Ecosystems (ANCE) Transplantation in a Non-Human Primate Model of Parkinson’s Disease

“…As outlined in Table 1, the present study is the logical continuation and extent of two previous reports on the ANCE approach applied to MPTP monkeys [26,27]. Brunet et al [27] and Bloch et al [26] included in their ANCE studies control animals and the fate of the implanted cells was reported.…”

“…This association is referred as autologous neural cell ecosystems (ANCE). In a therapeutic perspective, ANCE have been implanted in symptomatic NHP MPTP model [26]. All the ANCE implanted animals, except one, exhibited a statistically significant reduction of PD symptoms, while the two other groups of monkeys (sham-grafted and killed-cell grafted) did not show any improvement.…”

“…Interestingly, the implanted ANCE cells did not become tyrosine-hydroxylase (TH) positive cells. The positive behavioral effect of ANCE transplantation is thus most likely due to the release of neurotrophic factors [26,27].…”

“…Brunet et al [27] and Bloch et al [26] included in their ANCE studies control animals and the fate of the implanted cells was reported. Due to strict ethical guidelines restricting drastically the use of NHPs, controls were not repeated in the present study (Table 1).…”

“…The aim of the present study was rather to focus on an original issue, by investigating nigro-striatal dopaminergic function with 18F-DOPA PET scans in four adult macaque monkeys subjected to MPTP lesion and ANCE transplantation. Moreover, in order to extend the behavioral dimension as compared to earlier reports [26,27], the four MPTP monkeys subjected to ANCE of the present study were enrolled in an assessment of spontaneous motion activities, using an image analyzer system performing an objective evaluation of the motor symptoms [28]. As emphasized above (ethical restrictions) and capitalizing on the already demonstrated efficacy of ANCE transplantation in a symptomatic PD monkey model including control animals ( [26]; Table 1), all four macaques involved in the present study were subjected to a systemic MPTP lesion followed by ANCE transplantation.…”