title: Genetically engineered mesenchymal stem cells reduce behavioral deficits in the YAC 128 mouse model of Huntington's disease.
abstract: The purpose of this study was to evaluate the therapeutic effects of the transplantation of bone-marrow mesenchymal stem cells (MSCs), genetically engineered to over-express brain-derived neurotrophic factor (BDNF) or nerve growth factor (NGF) on motor deficits and neurodegeneration in YAC 128 transgenic mice. MSCs, harvested from mouse femurs, were genetically engineered to over-express BDNF and/or NGF and these cells, or the vehicle solution, were injected into the striata of four-month old YAC 128 transgenic and wild-type mice. Assessments of motor ability on the rotarod and the severity of clasping were made one day prior to transplantation and once monthly, thereafter, to determine the effects of the transplanted cells on motor function. The mice were sacrificed at 13-months of age for immunohistological examination. All YAC 128 mice receiving transplants had reduced clasping, relative to vehicle-treated YAC 128 mice, while YAC 128 mice that were transplanted with MSCs which were genetically engineered to over-express BDNF, had the longest latencies on the rotarod and the least amount of neuronal loss within the striatum of the YAC 128 mice. These results indicate that intrastriatal transplantation of MSCs that over-express BDNF may create an environment within the striatum that slows neurodegenerative processes and provides behavioral sparing in the YAC 128 mouse model of HD. Further research on the long-term safety and efficacy of this approach is needed before its potential clinical utility can be comprehensively assessed.
authors.affiliation: Field Neurosciences Institute Laboratory for Restorative Neurology, Central Michigan University, Mt. Pleasant, MI 48858, USA.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Dey
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Bombard
authors.forename: Bartholomew P
authors.initials: BP
authors.lastname: Roland
authors.forename: Stacy
authors.initials: S
authors.lastname: Davidson
authors.forename: Ming
authors.initials: M
authors.lastname: Lu
authors.forename: Julien
authors.initials: J
authors.lastname: Rossignol
authors.forename: Michael I
authors.initials: MI
authors.lastname: Sandstrom
authors.forename: Reid L
authors.initials: RL
authors.lastname: Skeel
authors.forename: Laurent
authors.initials: L
authors.lastname: Lescaudron
authors.forename: Gary L
authors.initials: GL
authors.lastname: Dunbar
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D018244:Chromosomes, Artificial, Yeast / Q000235:genetics*; D003342:Corpus Striatum / Q000473:pathology / Q000601:surgery; D004195:Disease Models, Animal; D005818:Genetic Engineering / Q000379:methods*; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009048:Motor Skills / Q000502:physiology*; D020932:Nerve Growth Factor / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D020932:Nerve Growth Factor