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

Author:

Emborg Marina E.12,Ebert Allison D.3,Moirano Jeff13,Peng Sun1,Suzuki Masatoshi3,Capowski Elizabeth3,Joers Valerie1,Roitberg Ben Z.14,Aebischer Patrick5,Svendsen Clive N.123

Affiliation:

1. Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI, USA

2. Department of Medical Physics, University of Wisconsin, Madison, WI, USA

3. Waisman Center, University of Wisconsin, Madison, WI, USA

4. Department of Neurosurgery, University of Illinois, Chicago, IL, USA

5. Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

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.

Publisher

SAGE Publications

Subject

Transplantation,Cell Biology,Biomedical Engineering

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