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- Parish, CL, et al.
(author)
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Midbrain dopaminergic neurogenesis and behavioural recovery in a salamander lesion-induced regeneration model
- 2007
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In: Development (Cambridge, England). - : The Company of Biologists. - 0950-1991 .- 1477-9129. ; 134:15, s. 2881-2887
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Journal article (peer-reviewed)abstract
- Death and lack of functional regeneration of midbrain dopaminergic (DA)neurons, decreased DA input in the target striatum and movement anomalies characterise Parkinson's disease (PD). There is currently no cure for PD. One way to promote recovery would be to induce or enhance DA neurogenesis. Whether DA neurogenesis occurs in the adult midbrain is a matter of debate. Here, we describe the creation of a salamander 6-hydroxydopamine model of PD to examine midbrain DA regeneration. We demonstrate a robust and complete regeneration of the mesencephalic and diencephalic DA system after elimination of DA neurons. Regeneration is contributed by DA neurogenesis, leads to histological restoration, and to full recovery of motor behaviour. Molecular analyses of the temporal expression pattern of DA determinants indicate that the regenerating DA neurons mature along a similar developmental program as their mammalian counterparts during embryogenesis. We also find that the adult salamander midbrain can reactivate radial glia-like ependymoglia cells that proliferate. The salamander model provides insights into the mechanisms of DA regeneration/neurogenesis and may contribute to the development of novel regenerative strategies for the mammalian brain.
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- Parish, CL, et al.
(author)
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Stem-cell-based strategies for the treatment of Parkinson's disease
- 2007
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In: Neuro-degenerative diseases. - : S. Karger AG. - 1660-2854 .- 1660-2862. ; 4:4, s. 339-347
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Journal article (peer-reviewed)abstract
- <i>Background: </i>Cell transplantation to replace lost neurons in neurodegenerative diseases such as Parkinson’s disease (PD) offers a hopeful prospect for many patients. Previously, fetal grafts have been shown to survive, integrate and induce functional recovery in PD patients. However, limited tissue availability has haltered the widespread use of this therapy and begs the demand for alternative tissue sources. In this regard, stem cells may constitute one such source. <i>Objective/Methods: </i>In this review we outline various types of stem cells currently available and provide an overview of their possible application for PD. We address not only the obvious possibility of using stem cells in cell replacement therapy but also the benefits of stem cell lines in drug discovery. <i>Results/Conclusion: </i>Stem cells carrying reporters or mutations in genes linked to familial PD are likely to contribute to the identification of new drug targets and subsequent development of new drugs for PD. Thus, stem cells are, and will be more so in the future, invaluable tools in the quest for new therapies against neurodegenerative diseases such as PD.
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| 5. |
- Parish, CL, et al.
(author)
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Wnt5a-treated midbrain neural stem cells improve dopamine cell replacement therapy in parkinsonian mice
- 2008
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In: Journal of Clinical Investigation. - 0021-9738. ; 118:1, s. 149-160
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Journal article (peer-reviewed)abstract
- Dopamine (DA) cell replacement therapy in Parkinson disease (PD) can be achieved using human fetal mesencephalic tissue; however, limited tissue availability has hindered further developments. Embryonic stem cells provide a promising alternative, but poor survival and risk of teratoma formation have prevented their clinical application. We present here a method for generating large numbers of DA neurons based on expanding and differentiating ventral midbrain (VM) neural stem cells/progenitors in the presence of key signals necessary for VM DA neuron development. Mouse VM neurospheres (VMNs) expanded with FGF2, differentiated with sonic hedgehog and FGF8, and transfected with Wnt5a (VMN-Wnt5a) generated 10-fold more DA neurons than did conventional FGF2-treated VMNs. VMN-Wnt5a cells exhibited the transcriptional and biochemical profiles and intrinsic electrophysiological properties of midbrain DA cells. Transplantation of these cells into parkinsonian mice resulted in significant cellular and functional recovery. Importantly, no tumors were detected and only a few transplanted grafts contained sporadic nestin-expressing progenitors. Our findings show that Wnt5a improves the differentiation and functional integration of stem cell-derived DA neurons in vivo and define Wnt5a-treated neural stem cells as an efficient and safe source of DA neurons for cell replacement therapy in PD.
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