Influence of cell preparation and target location on the behavioral recovery after striatal transplantation of fetal dopaminergic neurons in a primate model of Parkinson’s disease

Abstract

Surgeries involving transplantation of fetal dopamine (DA) neurons into the caudate-putamen of patients with Parkinson's disease (PD) have been performed in various clinical trials to examine a potential restoration of motor function. The absence of studies in nonhuman primates to define the best transplantation protocols have lead to the use of a broad variety of techniques that potentially could have a major impact on the clinical outcome. The effects of using different cell and tissue preparation, and surgical targets, remain unknown. For this purpose, 20 St. Kitts African Green Monkeys (AFG) rendered parkinsonian by i.m injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), were balanced into 4 groups and unilaterally grafted in the (a) caudate or (b) putamen with fetal ventral mesencephalic (VM) tissue as (c) solid pieces or as a (d) cell suspension. By 9 months post-transplantation all animals showed significant and similar behavioral improvement as determined by an UPDRS based PD scale. Postmortem analyses showed that VM transplants survived in all animals. They were located in both surgical target sites, producing a broad DA reinnervation of the targeted nuclei that could also extend to the non-grafted nucleus on the ipsilateral side. Although no differences between groups were found in survival of DA neurons or degree of DA reinnervation, there was a significant correlation between striatal reinnervation and behavioral recovery only in animals transplanted in the putamen surgical target. Additionally, there was in general, a stronger glial reaction to solid grafts than to cell suspensions. These studies provide data for the optimal time-course, cell preparation and surgical targets for systematic examinations of both potential benefits and side effects of dopamine neuron cell transplantation in primate models of PD.

Successful Function of Autologous iPSC-Derived Dopamine Neurons following Transplantation in a Non-Human Primate Model of Parkinson’s Disease

“…We observed a reduction in the hypokinesia subsection of the parkinsonian rating scale in MF25-04, from a score of 2 prior to transplantation (maximum possible score is 3) to a score of 0 at 12 months post-transplantation, and this remained stable at 0 until completion of the study (Table S1). Overall, the timecourse of functional recovery observed in MF25-04 was consistent with the developmental maturation, outgrowth and connectivity of analogous fetal non-human primate dopamine neurons (Redmond et al, 2008; Tsui and Isacson, 2011). No marked changes in global motor activity, MAP test time, or hypokinesia were observed in animals MF27-04 and MF66-02 at 1-2 years after autologous transplantation of differentiated CM-iPSCs (Figure 1A and Table S1), suggestive of insufficient survival of engrafted CM-iPSC derived midbrain dopamine neurons and reinnervation of the transplanted putamen (Grealish et al, 2010; Redmond et al, 2008).…”

“…Overall, the timecourse of functional recovery observed in MF25-04 was consistent with the developmental maturation, outgrowth and connectivity of analogous fetal non-human primate dopamine neurons (Redmond et al, 2008; Tsui and Isacson, 2011). No marked changes in global motor activity, MAP test time, or hypokinesia were observed in animals MF27-04 and MF66-02 at 1-2 years after autologous transplantation of differentiated CM-iPSCs (Figure 1A and Table S1), suggestive of insufficient survival of engrafted CM-iPSC derived midbrain dopamine neurons and reinnervation of the transplanted putamen (Grealish et al, 2010; Redmond et al, 2008). We also analyzed motor behavior in MPTP-lesioned CMs that received allogeneic transplantation with differentiated primate embryonic stem (ES) cells (Cyno-1) with no immunosuppression, as previously described (Sanchez-Pernaute et al, 2005), in which less than 50 surviving dopaminergic neurons were detected in the grafted putamen at post-mortem (termed the “non-surviving transplant” group) (n=3), and also in non-transplanted MPTP-lesioned CMs (n=4) (Table S1).…”

Transcriptome analysis reveals transmembrane targets on transplantable midbrain dopamine progenitors

“…Sorting on the basis of Alcam significantly increased not only the fraction of mDA neurons per unit of grafted tissue but also, the volume of host striatal territory innervated by the grafted mDA neurons. Both animal studies (26)(27)(28)(29)(30) and clinical observations (31-33) strongly suggest that the degree of recovery of motor function after grafting is closely related to the level of dopaminergic reinnervation of the striatum.…”

Neural transplants in patients with Huntington's disease undergo disease-like neuronal degeneration

“…At the electron microscopy level, synaptic contacts between glutamatergic axon varicosities and unlabeled dendrites within the graft were also observed. It is possible that the immune responses to solid grafts in the absence of immunosuppression (14,50), combined with the release of glutamate directly from microglia or glutamatergic cortico-striatal afferents, accelerated the degeneration process in grafted vs. host striatal neurons, as suggested in animal studies (51). Graft degenerative changes seen here are incompatible with clinical benefits after 10 years, vs. PD, where only 2 to 8% of grafted cells have ␣-synuclein inclusions (37)(38)(39), and clinical benefits lasted for 11 to 12 years in those patients (37,38).…”