title: Reductions in behavioral deficits and neuropathology in the R6/2 mouse model of Huntington's disease following transplantation of bone-marrow-derived mesenchymal stem cells is dependent on passage number.
abstract: BACKGROUND
  Huntington's disease (HD) is an autosomal dominant disorder caused by an expanded CAG repeat (greater than 38) on the short arm of chromosome 4, resulting in loss and dysfunction of neurons in the neostriatum and cortex, leading to cognitive decline, motor dysfunction, and death, typically occurring 15 to 20 years after the onset of motor symptoms. Although an effective treatment for HD has remained elusive, current studies using transplants of bone-marrow-derived mesenchymal stem cells provides considerable promise. This study further investigates the efficacy of these transplants with a focus on comparing how passage number of these cells may affect subsequent efficacy following transplantation.
  
  
  METHODS
  In this study, mesenchymal stem cells isolated from the bone-marrow of mice (BM MSCs), were labeled with Hoechst after low (3 to 8) or high (40 to 50) numbers of passages and then transplanted intrastriatally into 5-week-old R6/2 mice, which carries the N-terminal fragment of the human HD gene (145 to 155 repeats) and rapidly develops symptoms analogous to the human form of the disease.
  
  
  RESULTS
  It was observed that the transplanted cells survived and the R6/2 mice displayed significant behavioral and morphological sparing compared to untreated R6/2 mice, with R6/2 mice receiving high passage BM MSCs displaying fewer deficits than those receiving low-passage BM MSCs. These beneficial effects are likely due to trophic support, as an increase in brain derived neurotrophic factor mRNA expression was observed in the striatum following transplantation of BM MSCs.
  
  
  CONCLUSIONS
  The results from this study demonstrate that BM MSCs hold significant therapeutic value for HD, and that the amount of time the cells are exposed to in vitro culture conditions can alter their efficacy.
authors.affiliation: Field Neurosciences Laboratory for Restorative Neurology, Brain Research and Integrative Neuroscience Center, Program in Neuroscience, 1280 East Campus Drive, HP Building Room 2336, Mount Pleasant, MI, 48859, USA. rossi1j@cmich.edu.|College of Medicine, Central Michigan University, Mount Pleasant, MI, 48859, USA. rossi1j@cmich.edu.
authors.forename: Julien
authors.initials: J
authors.lastname: Rossignol
authors.affiliation: Field Neurosciences Laboratory for Restorative Neurology, Brain Research and Integrative Neuroscience Center, Program in Neuroscience, 1280 East Campus Drive, HP Building Room 2336, Mount Pleasant, MI, 48859, USA. fink1kd@cmich.edu.|Faculté des Science et des Techniques, Université de Nantes, 44300, Nantes, France. fink1kd@cmich.edu.|INSERM U1064, ITUN, 44093, Nantes, France. fink1kd@cmich.edu.
authors.forename: Kyle D
authors.initials: KD
authors.lastname: Fink
authors.affiliation: Field Neurosciences Laboratory for Restorative Neurology, Brain Research and Integrative Neuroscience Center, Program in Neuroscience, 1280 East Campus Drive, HP Building Room 2336, Mount Pleasant, MI, 48859, USA. crane1a@cmich.edu.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Crane
authors.affiliation: Field Neurosciences Laboratory for Restorative Neurology, Brain Research and Integrative Neuroscience Center, Program in Neuroscience, 1280 East Campus Drive, HP Building Room 2336, Mount Pleasant, MI, 48859, USA. davis3kk@cmich.edu.
authors.forename: Kendra K
authors.initials: KK
authors.lastname: Davis
authors.affiliation: Field Neurosciences Laboratory for Restorative Neurology, Brain Research and Integrative Neuroscience Center, Program in Neuroscience, 1280 East Campus Drive, HP Building Room 2336, Mount Pleasant, MI, 48859, USA. bomba1mc@cmich.edu.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Bombard
authors.affiliation: Field Neurosciences Laboratory for Restorative Neurology, Brain Research and Integrative Neuroscience Center, Program in Neuroscience, 1280 East Campus Drive, HP Building Room 2336, Mount Pleasant, MI, 48859, USA. clerc1s@cmich.edu.
authors.forename: Steven
authors.initials: S
authors.lastname: Clerc
authors.affiliation: Field Neurosciences Laboratory for Restorative Neurology, Brain Research and Integrative Neuroscience Center, Program in Neuroscience, 1280 East Campus Drive, HP Building Room 2336, Mount Pleasant, MI, 48859, USA. bavar1am@cmich.edu.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Bavar
authors.affiliation: Field Neurosciences Laboratory for Restorative Neurology, Brain Research and Integrative Neuroscience Center, Program in Neuroscience, 1280 East Campus Drive, HP Building Room 2336, Mount Pleasant, MI, 48859, USA. lowra1sa@cmich.edu.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Lowrance
authors.affiliation: Field Neurosciences Laboratory for Restorative Neurology, Brain Research and Integrative Neuroscience Center, Program in Neuroscience, 1280 East Campus Drive, HP Building Room 2336, Mount Pleasant, MI, 48859, USA. song1c@cmich.edu.
authors.forename: Cheng
authors.initials: C
authors.lastname: Song
authors.affiliation: Field Neurosciences Laboratory for Restorative Neurology, Brain Research and Integrative Neuroscience Center, Program in Neuroscience, 1280 East Campus Drive, HP Building Room 2336, Mount Pleasant, MI, 48859, USA. witte1sj@cmich.edu.
authors.forename: Steven
authors.initials: S
authors.lastname: Witte
authors.affiliation: Faculté des Science et des Techniques, Université de Nantes, 44300, Nantes, France. laurent.lescaudron@univ-nantes.fr.|INSERM U791, Laboratoire d'Ingenierie Osteo-Articulaire et Dentaire (LIOAD), 44042, Nantes, France. laurent.lescaudron@univ-nantes.fr.
authors.forename: Laurent
authors.initials: L
authors.lastname: Lescaudron
authors.affiliation: Field Neurosciences Laboratory for Restorative Neurology, Brain Research and Integrative Neuroscience Center, Program in Neuroscience, 1280 East Campus Drive, HP Building Room 2336, Mount Pleasant, MI, 48859, USA. dunba1g@cmich.edu.|Field Neurosciences Institute, Saginaw, MI, 48604, USA. dunba1g@cmich.edu.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Dunbar
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001854:Bone Marrow Cells / Q000166:cytology*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000628:therapy*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D014409:Tumor Necrosis Factor-alpha; D020932:Nerve Growth Factor; D020813:Receptor, trkB