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Piccini, P. et al. Dopamine release from nigral transplants visualized in vivo in a Parkinson's patient. Nature Neurosci. 2, 1137−1140

MRC Cyclotron Unit, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
Nature Neuroscience (Impact Factor: 14.98). 01/2000; 2(12):1137-40. DOI: 10.1038/16060
Source: PubMed

ABSTRACT Synaptic dopamine release from embryonic nigral transplants has been monitored in the striatum of a patient with Parkinson's disease using [11C]-raclopride positron emission tomography to measure dopamine D2 receptor occupancy by the endogenous transmitter. In this patient, who had received a transplant in the right putamen 10 years earlier, grafts had restored both basal and drug-induced dopamine release to normal levels. This was associated with sustained, marked clinical benefit and normalized levels of dopamine storage in the grafted putamen. Despite an ongoing disease process, grafted neurons can thus continue for a decade to store and release dopamine and give rise to substantial symptomatic relief.

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    • "The rapid pace of bench-to-bedside research in this field reflects the uniformly dismal prognosis, and the urgent demand of effective treatment for these common debilitating neurological conditions. In addition, sources of neural cells for clinical transplantation have been largely derived from fetal neural tissues, with earlier clinical trials using un-sorted, poorly-characterised neural tissues for the treatment of Parkinson Disease [14], [15]. The identification and characterisation of well-defined human NSC raises the prospect of increasing the efficiency of a cellular transplantation approach for treating different neural injuries, through lineage-specific cellular replacement, the delivery of trophic factors, immune modulation and reduction of inflammation [16], [17], [18]. "
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    ABSTRACT: Neural stem/progenitor cells (NSC) have the potential for treatment of a wide range of neurological diseases such as Parkinson Disease and multiple sclerosis. Currently, NSC have been isolated only from hippocampus and subventricular zone (SVZ) of the adult brain. It is not known whether NSC can be found in all parts of the developing mid-trimester central nervous system (CNS) when the brain undergoes massive transformation and growth. Multipotent NSC from the mid-trimester cerebra, thalamus, SVZ, hippocampus, thalamus, cerebellum, brain stem and spinal cord can be derived and propagated as clonal neurospheres with increasing frequencies with increasing gestations. These NSC can undergo multi-lineage differentiation both in vitro and in vivo, and engraft in a developmental murine model. Regionally-derived NSC are phenotypically distinct, with hippocampal NSC having a significantly higher neurogenic potential (53.6%) over other sources (range of 0%-27.5%, p<0.004). Whole genome expression analysis showed differential gene expression between these regionally-derived NSC, which involved the Notch, epidermal growth factor as well as interleukin pathways. We have shown the presence of phenotypically-distinct regionally-derived NSC from the mid-trimester CNS, which may reflect the ontological differences occurring within the CNS. Aside from informing on the role of such cells during fetal growth, they may be useful for different cellular therapy applications.
    PLoS ONE 09/2014; 9(9):e105985. DOI:10.1371/journal.pone.0105985 · 3.23 Impact Factor
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    • "Various kinds of cells have been investigated for transplantation studies (Corti et al., 2004; Garbuzova-Davis et al., 2008; Iwanami et al., 2005; Piccini et al., 1999). Neuronal cells are probably the most relevant cell type for ALS treatment, but such cells suffer from a limited supply, ethical issues, and/or invasive harvest from human donors. "
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    ABSTRACT: Transplantation of glial-rich neural progenitors has been demonstrated to attenuate motor neuron degeneration and disease progression in rodent models of mutant superoxide dismutase 1 (SOD1)-mediated amyotrophic lateral sclerosis (ALS). However, translation of these results into a clinical setting requires a renewable human cell source. Here, we derived glial-rich neural progenitors from human iPSCs and transplanted them into the lumbar spinal cord of ALS mouse models. The transplanted cells differentiated into astrocytes, and the treated mouse group showed prolonged lifespan. Our data suggest a potential therapeutic mechanism via activation of AKT signal. The results demonstrated the efficacy of cell therapy for ALS by the use of human iPSCs as cell source.
    Stem Cell Reports 08/2014; 3(2). DOI:10.1016/j.stemcr.2014.05.017 · 5.64 Impact Factor
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    • "A number of explorative studies using human fetal, ventral mesencephalic (VM) dopaminergic neurons have shown that intrastriatal transplantation may become an effective future treatment for patients with PD [2]–[5]. However, the use of human fetal tissue is compromised by ethical concerns, suboptimal survival and integration of grafted DA neurons, development of graft-induced dyskinesias in some patients as well as practical problems and logistics related to the procurement and storage of human donor tissue [6]–[10]. "
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    ABSTRACT: Neural stem cells (NSCs) constitute a promising source of cells for transplantation in Parkinson's disease (PD), but protocols for controlled dopaminergic differentiation are not yet available. Here we investigated the influence of oxygen on dopaminergic differentiation of human fetal NSCs derived from the midbrain and forebrain. Cells were differentiated for 10 days in vitro at low, physiological (3%) versus high, atmospheric (20%) oxygen tension. Low oxygen resulted in upregulation of vascular endothelial growth factor and increased the proportion of tyrosine hydroxylase-immunoreactive (TH-ir) cells in both types of cultures (midbrain: 9.1±0.5 and 17.1±0.4 (P<0.001); forebrain: 1.9±0.4 and 3.9±0.6 (P<0.01) percent of total cells). Regardless of oxygen levels, the content of TH-ir cells with mature neuronal morphologies was higher for midbrain as compared to forebrain cultures. Proliferative Ki67-ir cells were found in both types of cultures, but the relative proportion of these cells was significantly higher for forebrain NSCs cultured at low, as compared to high, oxygen tension. No such difference was detected for midbrain-derived cells. Western blot analysis revealed that low oxygen enhanced β-tubulin III and GFAP expression in both cultures. Up-regulation of β-tubulin III was most pronounced for midbrain cells, whereas GFAP expression was higher in forebrain as compared to midbrain cells. NSCs from both brain regions displayed less cell death when cultured at low oxygen tension. Following mictrotransplantation into mouse striatal slice cultures predifferentiated midbrain NSCs were found to proliferate and differentiate into substantial numbers of TH-ir neurons with mature neuronal morphologies, particularly at low oxygen. In contrast, predifferentiated forebrain NSCs microtransplanted using identical conditions displayed little proliferation and contained few TH-ir cells, all of which had an immature appearance. Our data may reflect differences in dopaminergic differentiation capacity and region-specific requirements of NSCs, with the dopamine-depleted striatum cultured at low oxygen offering an attractive micro-environment for midbrain NSCs.
    PLoS ONE 05/2014; 9(5):e96465. DOI:10.1371/journal.pone.0096465 · 3.23 Impact Factor
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