Activation of endogenous neurogenesis and neurorescue mechanism by human mesenchymal stem cells transplantation in an experimental model of Parkinson's Disease

Stem cells have been increasingly recognized as a valuable tool to replace or support cells damaged by neurodegenerative diseases, such as Parkinson’s Disease (PD). In the present study, we have used a rodent model of PD based on the unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA), a procedure that causes a progressive and retrograde degeneration of the nigrostriatal pathway, to investigate the survival and effect of transplanted human mesenchymal stem cells (hMSCs). Male Sprague Dawley rats received a stereotaxic injection of 6-OHDA in the right striatum. Five days later, commercial hMSCs, previously characterized for cellular behavior and resistance to chronic or acute 6OHDA exposition in vitro, were labeled with Hoechst 33258 and transplanted in the right lesioned striatum. To avoid rejection of the xenograft, animals were treated with cyclosporine through the entire experimental procedure. We performed immunohistochemical analysis to characterize the survival of dopaminegic terminals in the striatum and the phenotype of the transplanted hMSCs in situ, as well as the possible neurogenic activation in the Subventricular Zone (SVZ), 23 days after implantation. Grafted hMSCs slightly differentiated towards a neuro-glial (GFAP+) phenotype. In addition, they regionally sustained survival of Tyrosine Hydroxylase positive terminals and, dose dependently, enhanced neurogenesis. As a matter of fact, intensity signal of proliferative markers (Ki67/Proliferating Nuclear Marker, PCNA), as well as the number of Nestin immunolabeled cells, significantly augmented, showing migratory potential towards the damaged striata, with respect to controls. Conversely, the number and activation status of astrocytes were not affected by transplantation. A modulatory effect of grafted cells on cytokine/ chemokine release seemed to play a major role in the reported phenomena. Our data support the use of autologous hMSCs as a valuable tool for development of neuroreparative strategies in PD based on the activation of endogenous neurogenesis and rescue mechanisms.