title: Neural stem cells transplanted in a mouse model of Parkinson's disease differentiate to neuronal phenotypes and reduce rotational deficit.
abstract: The most prominent pathological feature in Parkinson's disease (PD) is the progressive and selective loss of mesencephalic dopaminergic neurons of the nigrostriatal tract. The present study was conducted in order to investigate whether naive and or genetically modified neural stem/precursor cells (NPCs) can survive, differentiate and functionally integrate in the lesioned striatum. To this end, stereotaxic injections of 6-OHDA in the right ascending nigrostriatal dopaminergic pathway of mice and subsequent NPC transplantations were performed, followed by apomorphine-induced rotations and double-immunofluorescence experiments. Our results demonstrate that transplanted embryonic NPCs derived from the cortical ventricular zone of E14.5 transgenic mouse embryos expressing the green fluorescent protein (GFP) under control of the beta-actin promoter and cultured as neurospheres can survive in the host striatum for at least three weeks after transplantation. The percentage of surviving GFP-positive cells in the host striatum ranges from 0.2% to 0.6% of the total transplanted NPCs. Grafted cells functionally integrate in the striatum, as indicated by the statistically significant decrease of contralateral rotations after apomorphine treatment. Furthermore, we show that within the striatal environment GFP-positive cells differentiate into beta-III tubulin-expressing neurons, but not glial cells. Most importantly, GFP-positive cells further differentiate to dopaminergic (TH-positive) and medium size spiny (DARPP-32- positive) neuronal phenotypes. Over-expression of the cell cycle exit and neuronal differentiation protein Cend1 in NPCs enhances the generation of GABAergic, but not dopaminergic, neuronal phenotypes after grafting in the lesioned striatum. Our results encourage the development of strategies involving NPC transplantation for the treatment of neurodegenerative diseases.
authors.affiliation: Department of Physiology, Medical School, University of Patras, Patras, Greece.
authors.forename: Despina
authors.initials: D
authors.lastname: Ziavra
authors.forename: Georgia
authors.initials: G
authors.lastname: Makri
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Giompres
authors.forename: Stavros
authors.initials: S
authors.lastname: Taraviras
authors.forename: Dimitra
authors.initials: D
authors.lastname: Thomaidou
authors.forename: Rebecca
authors.initials: R
authors.lastname: Matsas
authors.forename: Ada
authors.initials: A
authors.lastname: Mitsacos
authors.forename: Elias D
authors.initials: ED
authors.lastname: Kouvelas
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use; D001058:Apomorphine / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000166:cytology; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006085:Graft Survival; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016627:Oxidopamine; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology*; D014404:Tubulin / Q000235:genetics / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; C496858:Cend1 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D014404:Tubulin; C462941:beta3 tubulin, mouse; D049452:Green Fluorescent Proteins; D016627:Oxidopamine; D001058:Apomorphine