Abstract
BackgroundGenetically engineered neural stem cell (NSC) lines are promising vectors for the treatment of neurodegenerative diseases, particularly Parkinson's disease (PD). Neurturin (NTN), a member of the glial cell line-derived neurotrophic factor (GDNF) family, has been demonstrated to act specifically on mesencephalic dopaminergic neurons, suggesting its therapeutic potential for PD. In our previous work, we demonstrated that NTN-overexpressing c17.2 NSCs exerted dopaminergic neuroprotection in a rat model of PD. In this study, we transplanted NTN-c17.2 into the striatum of the 6-hydroxydopamine (6-OHDA) PD model to further determine the regenerative effect of NTN-c17.2 on the rat models of PD.ResultsAfter intrastriatal grafting, NTN-c17.2 cells differentiated and gradually downregulated nestin expression, while the grafts stably overexpressed NTN. Further, an observation of rotational behavior and the contents of neurotransmitters tested by high-performance liquid chromatography showed that the regenerative effect of the NTN-c17.2 group was significantly better than that of the Mock-c17.2 group, and the regenerative effect of the Mock-c17.2 group was better than that of the PBS group. Further research through reverse-transcriptase polymerase chain reaction assays and in vivo histology revealed that the regenerative effect of Mock-c17.2 and NTN-c17.2 cell grafts may be attributed to the ability of NSCs to produce neurotrophic factors and differentiate into tyrosine hydroxylase-positive cells.ConclusionThe transplantation of NTN-c17.2 can exert neuroregenerative effects in the rat model of PD, and the delivery of NTN by NSCs may constitute a very useful strategy in the treatment of PD.
Highlights
Engineered neural stem cell (NSC) lines are promising vectors for the treatment of neurodegenerative diseases, Parkinson's disease (PD)
Engineering and characterization of NTN expression in NSCs The c17.2 mouse NSCs were transfected with the pcDNA3.1-Hygro-NTN vector to generate NTN-c17.2 cells or the pcDNA3.1-Hygro vector to generate Mock-c17.2 cells
Detection of NTN protein expression in NSCs after intrastriatal grafting in vivo NTN and nestin protein-expressing cells of the corpus striatum were identified by immunohistochemistry 4.5, 30, and 120 d after the animals were transplanted with NTN-c17.2 cells (Fig. 1A–F)
Summary
Engineered neural stem cell (NSC) lines are promising vectors for the treatment of neurodegenerative diseases, Parkinson's disease (PD). Neurturin (NTN), a member of the glial cell line-derived neurotrophic factor (GDNF) family, has been demonstrated to act on mesencephalic dopaminergic neurons, suggesting its therapeutic potential for PD. A pathologic feature of Parkinson's disease (PD) is the loss of melanized dopaminergic neurons within the substantia nigra (SN) pars compacta coupled with depletion of striatal dopamine. Researchers have searched for preventative and curative strategies, leading to the development of certain novel therapeutic approaches Most of these approaches are based on strategies of neuroprotection, whereby dopaminergic neurons are prevented from dying, and neuroregeneration, whereby dead or injured neurons are supplemented by transplantation [4,5,6,7]. Based on the neuroprotective effects on nigrostriatal DA neurons, NTN has been suggested as a candidate for the treatment of PD
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