Multitracer assessment of dopamine function after transplantation of embryonic stem cell‐derived neural stem cells in a primate model of Parkinson's disease

Abstract

The ability of primate embryonic stem (ES) cells to differentiate into dopamine (DA)-synthesizing neurons has raised hopes of creating novel cell therapies for Parkinson's disease (PD). As the primary purpose of cell transplantation in PD is restoration of dopaminergic neurotransmission in the striatum, in vivo assessment of DA function after grafting is necessary to achieve better therapeutic effects. A chronic model of PD was produced in two cynomolgus monkeys (M-1 and M-2) by systemic administration of neurotoxin. Neural stem cells (NSCs) derived from cynomolgus ES cells were implanted unilaterally in the putamen. To evaluate DA-specific functions, we used multiple [(11)C]-labeled positron emission tomography (PET) tracers, including [beta-(11)C]L-3,4-dihydroxyphenylalanine (L-[beta-(11)C]DOPA, DA precursor ligand), [(11)C]-2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane ([(11)C]beta-CFT, DA transporter ligand) and [(11)C]raclopride (D(2) receptor ligand). At 12 weeks after grafting NSCs, PET demonstrated significantly increased uptake of L-[beta-(11)C]DOPA (M-1:41%, M-2:61%) and [(11)C]beta-CFT (M-1:31%, M-2:36%) uptake in the grafted putamen. In addition, methamphetamine challenge in M-2 induced reduced [(11)C]raclopride binding (16%) in the transplanted putamen, suggesting release of DA. These results show that transplantation of NSCs derived from cynomolgus monkey ES cells can restore DA function in the putamen of a primate model of PD. PET with multitracers is useful for functional studies in developing cell-based therapies against PD.

PET Imaging of Mitochondrial Complex I with 18F-BCPP-EF in the Brains of MPTP-Treated Monkeys

“…We previously confirmed that the degeneration of nigrostriatal dopamine neurons was induced by the intravenous administration of MPTP to monkeys over a period of several months and resulted in impaired presynaptic dopamine parameters, as determined by DAT availability, dopamine synthesis, and tyrosine hydroxylase immunoreactivity in the brain (9,10). A previous study reported that although plotting the striatal MTGA Ki values of 11 C-6MemTyr, b-11 C-L-DOPA, and 18 F-FDOPA against the BP ND of 11 C-b-CFT in the striatum of monkeys revealed positive correlations, the Ki value of 11 C-6MemTyr provided greater correlation coefficients than b-11 C-L-DOPA and 18 F-FDOPA (10).…”

“…Five male normal and 5 MPTP-treated cynomolgus monkeys (Macaca fascicularis; age range, 2.8-3.3 y; weight range, 2.0-3.5 kg) were subjected to PET scans (9,10). MPTP at doses ranging from 0.2 to 0.4 mg/kg of free base in phosphate-buffered saline was injected intravenously once per week over a 4-mo period until a stable parkinsonian syndrome was observed.…”

Uncertain Translation, Uncertain Benefit and Uncertain Risk: Ethical Challenges Facing First‐in‐human Trials of Induced Pluripotent Stem (Ips) Cells

“…In the 2009 study by Muramatsu and colleagues, dopaminergic neurons differentiated from primate embryonic stem cells were transplanted into MPTP-lesioned cynomolous monkeys. 21 Following transplantation, PET scans showed restored dopamine function in the brain, although there was only modest functional recovery at 12 weeks after implantation.…”

Increase of sensitivity to mechanical stimulus after transplantation of murine induced pluripotent stem cell–derived astrocytes in a rat spinal cord injury model

“…30 Recently, dopaminergic neurons derived from monkey ESCs (using the NSS method) were transplanted into a monkey model of Parkinson disease, and the technique promoted locomotion. 24 We hypothesized that the NSS method could also be applied to iPSCs to achieve targeted differentiation into neuronal cells.…”

“…Using the NSS method, dopaminergic neurons have been derived from monkey ESCs and have been transplanted to monkeys with Parkinson disease, resulting in improved motor function. 24 Human neurons, generated from ESCs by the NSS method, have been shown to survive in murine brains following xenotransplantation. 34 Nakayama and colleagues 29 reported that the NSS method was very efficient because each ESC generated 1000 NSCs in an 11-day period.…”