title: GDNF-secreting mesenchymal stem cells provide localized neuroprotection in an inflammation-driven rat model of Parkinson's disease.
abstract: Constraints involving the delivery method of glial cell line-derived neurotrophic factor (GDNF) have hampered its efficacy as a neuroprotectant in Parkinson's disease. Ex vivo gene therapy, in which suitable cells, such as bone marrow-derived mesenchymal stem cells (MSCs), are genetically engineered to overexpress GDNF (GDNF-MSCs) prior to transplantation may be more beneficial than direct brain infusion of the neurotrophin. Previously, GDNF-MSCs have been assessed in the commonly employed 6-hydroxydopamine neurotoxic model of Parkinson's disease. In this study however, we used an emerging inflammatory model of Parkinson's disease (the lipopolysaccharide (LPS) model) to assess the ability of transplanted GDNF-MSCs to protect against LPS-induced neuroinflammation, neurodegeneration and behavioral impairment. Thirty male Sprague-Dawley rats were used in this experiment. Rats were performance matched based on baseline motor function tests into three groups (LPS lesion only, LPS lesion+GFP-MSCs, LPS lesion+GDNF-MSCs; n=10/group). Both cell groups received a unilateral intra-striatal transplant of either 200,000 GDNF-MSCs or 200,000 GFP-MSCs (as a control). One day post-transplantation, all rats received a unilateral intra-nigral infusion of LPS (10 μg in 2 μl sterile saline). Rats were sacrificed by transcardial perfusion-fixation and their brains were used for post mortem quantitative immunohistochemistry. Injection of LPS into the substantia nigra induced a pronounced local inflammatory response which resulted in 20% loss of nigrostriatal dopaminergic neurons and impaired contralateral motor function. Following transplantation of GDNF-MSCs to the striatum, dense areas of TH-positive staining directly proximal to the transplant site were observed. Most importantly, this effect was observed only in the GDNF-MSC transplanted group and not the GFP-MSC transplanted group demonstrating protection and/or sprouting of the dopaminergic terminals induced by the secreted GDNF. This study is the first to highlight the neurotrophic capability of GDNF in the inflammation-driven LPS model and, while future studies will endeavor to improve this approach by increasing cell survival, this work highlights the potential of GDNF delivery by ex vivo gene therapy using MSCs.
authors.affiliation: Pharmacology & Therapeutics, National University of Ireland, Galway, Ireland; NCBES Galway Neuroscience Centre, National University of Ireland, Galway, Ireland.
authors.forename: D B
authors.initials: DB
authors.lastname: Hoban
authors.affiliation: The Regenerative Medicine Institute, National University of Ireland, Galway, Ireland.
authors.forename: L
authors.initials: L
authors.lastname: Howard
authors.affiliation: Pharmacology & Therapeutics, National University of Ireland, Galway, Ireland; NCBES Galway Neuroscience Centre, National University of Ireland, Galway, Ireland. Electronic address: eilis.dowd@nuigalway.ie.
authors.forename: E
authors.initials: E
authors.lastname: Dowd
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D004195:Disease Models, Animal; D005552:Forelimb / Q000503:physiopathology; D007839:Functional Laterality / Q000187:drug effects; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism / Q000627:therapeutic use; D010300:Parkinson Disease / Q000209:etiology / Q000601:surgery*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D013378:Substantia Nigra / Q000187:drug effects; D013997:Time Factors; D014161:Transduction, Genetic; D014738:Vibrissae / Q000294:innervation
chemical_list: D039481:CD11b Antigen; D051100:Glial Cell Line-Derived Neurotrophic Factor; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins
keywords: GDNF; Parkinson’s disease; inflammation; lipopolysaccharide; mesenchymal stem cells; neuroprotection