Although implantation of fetal dopamine (DA) neurons can reduce parkinsonism in patients, current methods are rudimentary, and a reliable donor cell source is lacking. We show that transplanting low doses of undifferentiated mouse embryonic stem (ES) cells into the rat striatum results in a proliferation of ES cells into fully differentiated DA neurons. ES cell-derived DA neurons caused gradual and sustained behavioral restoration of DA-mediated motor asymmetry. Behavioral recovery paralleled in vivo positron emission tomography and functional magnetic resonance imaging data demonstrating DA-mediated hemodynamic changes in the striatum and associated brain circuitry. These results demonstrate that transplanted ES cells can develop spontaneously into DA neurons. Such DA neurons can restore cerebral function and behavior in an animal model of Parkinson's disease. P arkinson's disease (PD) is a degenerative disorder characterized by a loss of midbrain dopamine (DA) neurons with a subsequent reduction in striatal DA (1). Pharmacological treatment with L-DOPA works initially, but reduced efficacy and development of motor complications requires treatment alternatives such as deep brain stimulation and fetal DA neuron transplantation (2). There is evidence both from animal models and clinical investigations showing that fetal DA neurons can produce symptomatic relief (3-6). Technical and ethical difficulties in obtaining sufficient and appropriate donor fetal brain tissue have limited the application of this new therapy.Previous work showed that DA neurons can be produced in vitro from ventral mesencephalic (VM) precursor cells (7). A problem using expanded fetal VM precursors (7) is the low in vivo survival rate of 3-5% of the grafted DA neurons, which eliminates the actual gain by in vitro cell number expansion compared with fresh (unexpanded) fetal day-12 VM (7,8).Embryonic stem (ES) cells have many characteristics required for an optimal cell source for cell-replacement therapy (9, 10). ES cells are self-renewing and multipotent cells derived from the inner cell mass of the preimplantation blastocyst (11). We have shown previously that mouse ES cells transplanted to normal mice or 6-hydroxydopamine (OHDA)-lesioned rats can differentiate spontaneously into tyrosine hydroxylase (TH)-positive and serotonin (5HT)-positive neurons. This differentiation is likely not caused by a specific inductive signal from the host brain, because similar neuronal differentiation occurs after placement in the kidney capsule (11). In our previous study (11), grafts frequently showed heterogeneous morphology and often became very large, disrupting the cytoarchitecture at the implantation site, which prevented the possibility for functional integration. Because neurons develop from ES cells even when implanted outside the central nervous system (11) and ectoderm develops into neural tissue when cellto-cell communication is disrupted by dissociation of the cells (12-14), we hypothesized that dilution of ES cells into single-cell suspension...
We investigated the microglial response to progressive dopamine neuron degeneration using in vivo positron emission tomography (PET) imaging and postmortem analyses in a Parkinson's disease (PD) rat model induced by unilateral (right side) intrastriatal administration of 6-hydroxydopamine (6-OHDA). Degeneration of the dopamine system was monitored by PET imaging of presynaptic dopamine transporters using a specific ligand (11)C-CFT (2beta-carbomethoxy-3beta-(4-fluorophenyl) tropane). Binding of (11)C-CFT was markedly reduced in the striatum indicating dopaminergic degeneration. Parallel PET studies of (11)C-PK11195 (1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3 isoquinoline carboxamide) (specific ligand for activated microglia) showed increased binding in the striatum and substantia nigra indicative of a microglial response. Postmortem immunohistochemical analyses were performed with antibodies against CR3 for microglia/macrophage activation. Using a qualitative postmortem index for microglial activation we found an initially focal, then widespread microglial response at striatal and nigral levels at 4 weeks postlesion. These data support the hypothesis that inflammation is a significant component of progressive dopaminergic degeneration that can be monitored by PET imaging.
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