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Free Content GDNF-Secreting Human Neural Progenitor Cells Increase Tyrosine Hydroxylase and VMAT2 Expression in MPTP-Treated Cynomolgus Monkeys

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Abstract:

Human neural progenitor cells (hNPCs) have been proposed as a potential source of cells for ex vivo gene therapy. In this pilot study, three 5-year-old female cynomolgus monkeys received a single intracarotid infusion of MPTP, followed 1 week later by MRI-guided stereotaxic intrastriatal and intranigral injections of male hNPCs transgenic for GDNF. Immunosupression with oral cyclosporine (30–40 mg/kg) began 48 h before hNPC transplants and continued throughout the study. We monitored the animals using a clinical rating scale (CRS). Three months postsurgery, we euthanized the animals by transcardiac perfusion, then retrieved and processed their brains for morphological analysis. Our findings include the following. 1) hNPCs survived and produced GDNF in all animals 3 months postsurgery. 2) hNPCs remained in the areas of injection as observed by GDNF immunostaining and in situ hybridization for the human Y chromosome. 3) A “halo” of GDNF expression was observed diffusing from the center of the graft out into the surrounding area. 4) We observed increased TH- and VMAT2-positive fibers in areas of GDNF delivery in two of the three animals. The two animals with TH- and VMAT2-positive fibers also showed reductions in their CRS scores. 5) Some GFAP-positive perivascular cuffing was found in transplanted areas. 6) General blood chemistry and necropsies did not reveal any abnormalities. Therefore, we conclude that hNPCs releasing GDNF may be a possible alternative for intracerebral trophic factor delivery in Parkinson's disease.

Keywords: Dopamine; Neuroprotection; Parkinson's disease; Stem cells; Trophic factors

Document Type: Research Article

DOI: https://doi.org/10.3727/096368908784423300

Affiliations: 1: Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI, USA, Department of Medical Physics, University of Wisconsin, Madison, WI, USA 2: Waisman Center, University of Wisconsin, Madison, WI, USA 3: Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI, USA, §Department of Anatomy, University of Wisconsin, Madison, WI, USA 4: Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI, USA 5: Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI, USA, Department of Neurosurgery, University of Illinois, Chicago, IL, USA 6: Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland 7: Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI, USA, Department of Medical Physics, University of Wisconsin, Madison, WI, USA, Waisman Center, University of Wisconsin, Madison, WI, USA

Publication date: 2008-04-01

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  • Cell Transplantation publishes original, peer-reviewed research and review articles on the subject of cell transplantation and its application to human diseases. To ensure high-quality contributions from all areas of transplantation, separate section editors and editorial boards have been established. Articles deal with a wide range of topics including physiological, medical, preclinical, tissue engineering, and device-oriented aspects of transplantation of nervous system, endocrine, growth factor-secreting, bone marrow, epithelial, endothelial, and genetically engineered cells, among others. Basic clinical studies and immunological research papers are also featured. To provide complete coverage of this revolutionary field, Cell Transplantation will report on relevant technological advances, and ethical and regulatory considerations of cell transplants. Cell Transplantation is now an Open Access journal starting with volume 18 in 2009, and therefore there will be an inexpensive publication charge, which is dependent on the number of pages, in addition to the charge for color figures. This will allow work to be disseminated to a wider audience and also entitle the corresponding author to a free PDF, as well as prepublication of an unedited version of the manuscript.
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