Intrastriatal Transplantation of Human Neural Stem Cells Restores the Impaired Subventricular Zone in Parkinsonian Mice

Cell replacement therapy using neural stem cells (NSCs) transplantation has recently emerged as a promising method of Parkinson's disease (PD) treatment; however, the underlying mechanisms are not fully understood. To gain new insights into the mechanisms of 6-hydroxydopamine (6-OHDA)-induced lesioning and therapeutic efficacy of human NSCs (hNSCs) transplantation, the striatum (ST) of intrastriatal 6-OHDA-injected parkinsonian mice were unilaterally engrafted with undifferentiated hNSCs. A high-throughput quantitative proteomic approach was used to characterize the proteome profiles of PD-related brain regions such as the SN, ST, olfactory bulb, and subventricular zone (SVZ) in these mice. The abundance of more than 5,000 proteins in each region was determined with high confidence in this study, which is the most extensive proteomic study of PD mouse models to date. In addition to disruption of the DA system, the quantitative analysis demonstrated profound disturbance of the SVZ proteome after 6-OHDA insult. After hNSC engraftment, the SVZ proteome was restored and the astrocytes in the ST were greatly activated, accompanied by an increase in neurotrophic factors. Furthermore, bioinformatics analysis demonstrated that the changes in the proteome were not caused by the proliferation of hNSCs or their progeny, but rather by the reaction of endogenous stem cells. Overall, this study elucidates the unexpected role of SVZ cells in PD progress and treatment, thereby providing new therapeutic targets for PD. Stem Cells 2017;35:1519-1531.