Dopaminergic Neuron-Like Cells Derived from Bone Marrow Mesenchymal Stem Cells by Lmx1α and Neurturin Overexpression for Autologous Cytotherapy in Hemiparkinsonian Rhesus Monkeys

Title:Dopaminergic Neuron-Like Cells Derived from Bone Marrow Mesenchymal Stem Cells by Lmx1α and Neurturin Overexpression for Autologous Cytotherapy in Hemiparkinsonian Rhesus Monkeys

Volume: 10 Issue: 2

Author(s): Wan-Pu Wang, Zhan-Long He, Shuai-Yao Lu, Min Yan, Yan Zhou, Tian-Hong Xie, Na Yin, Dong-Hong Tang, Hong-Jun Li and Mao-Sheng Sun

Affiliation:

Keywords: Differentiation, gene therapy, LIM homeobox transcription factor 1α, neurturin, Parkinson’s disease, rhesus bone marrow mesenchymal stem cells, transplantation.

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 MPTPlesioned 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.

Cite this article as:

Wang Wan-Pu, He Zhan-Long, Lu Shuai-Yao, Yan Min, Zhou Yan, Xie Tian-Hong, Yin Na, Tang Dong-Hong, Li Hong-Jun and Sun Mao-Sheng, Dopaminergic Neuron-Like Cells Derived from Bone Marrow Mesenchymal Stem Cells by Lmx1α and Neurturin Overexpression for Autologous Cytotherapy in Hemiparkinsonian Rhesus Monkeys, Current Stem Cell Research & Therapy 2015; 10 (2) . https://dx.doi.org/10.2174/1574888X09666141010102533