title: Dopaminergic neuron-like cells derived from bone marrow mesenchymal stem cells by Lmx1α and neurturin overexpression for autologous cytotherapy in hemiparkinsonian rhesus monkeys.
abstract: Bone marrow-derived mesenchymal stem cells hold great potential for cytotherapeutics of neurodegenerative disorders, including Parkinson's disease. The neurotrophic factor neurturin can rescue dopaminergic neurons damaged during the disease process. Lmx1α can promote mesencephalic dopaminergic differentiation during embryogenesis. In this study, we tested a cytotherapeutic strategy combining NTN/Lmx1α gene therapy and cell transplantation to ameliorate disease progression in hemiparkinsonian rhesus. Rhesus BMSCs were prepared for autologous grafting by transfection with recombinant adenoviral vectors expressing secreted NTN and Lmx1α,and cultured in the presence of induce factors, particularly the Lmx1α regulatory factor sonic hedgehog, to guide dopaminergic differentiation. These induced rh-BMSCs exhibited gene/protein expression phenotypes resembling nigral dopaminergic neurons. They survived and retained dopaminergic function following stereotaxic injection into the MPTP-lesioned right-side substantia nigra as indicated by SPECT measurement of DAT activity. Injected cells preserved and supplemented the remaining endogenous population of dopamine neurons (TH-positive cell ipsilateral/contralateral ratio was 56.81% ± 7.28% vs. 3.86%±1.22% in vehicle-injected controls; p<0.05). Cell injection also partially restored motor function and reduce apomorphine-evoked rotation (p<0.05). Moreover, function recovery occurred earlier than in previous studies on injected BMSCs. Our findings demonstrate a promising strategy for restoration of PD-associated motor dysfunction by transplantation of autologous BMSCs overexpressing NTN/Lmx1α.
authors.forename: Wan-Pu
authors.initials: WP
authors.lastname: Wang
authors.forename: Zhan-Long
authors.initials: ZL
authors.lastname: He
authors.forename: Shuai-Yao
authors.initials: SY
authors.lastname: Lu
authors.forename: Min
authors.initials: M
authors.lastname: Yan
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Tian-Hong
authors.initials: TH
authors.lastname: Xie
authors.forename: Na
authors.initials: N
authors.lastname: Yin
authors.forename: Wen-Ju
authors.initials: WJ
authors.lastname: Wang
authors.forename: Dong-Hong
authors.initials: DH
authors.lastname: Tang
authors.forename: Hong-Jun
authors.initials: HJ
authors.lastname: Li
authors.forename: Mao-Sheng
authors.initials: MS
authors.lastname: Sun
mesh_terms: D000818:Animals; D002642:Chick Embryo; D059290:Dopaminergic Neurons / Q000502:physiology*; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D008253:Macaca mulatta; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D055495:Neurogenesis; D051101:Neurturin / Q000096:biosynthesis* / Q000235:genetics; D010302:Parkinson Disease, Secondary / Q000503:physiopathology / Q000628:therapy*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014182:Transplantation, Autologous
chemical_list: D060850:LIM-Homeodomain Proteins; C078021:LMX1A protein, human; D051101:Neurturin; D014157:Transcription Factors