Differential effects of neural stem cell therapy in adult and middle-aged Parkinsonian mice

Abstract

Parkinson´s disease (PD), the second most common neurodegenerative disease in the world, is characterized by the death or impairment of dopaminergic neurons (DAn) in the substantia nigra pars compacta (SNpc) and the depletion of dopamine in the striatum (Str). Symptoms of the disease include tremors, rigidity, bradykinesia, and postural instability. Currently, there is no cure for PD, and treatments only help to reduce the symptoms of the disease, and do not repair or replace the DAn damaged or lost in PD. Cell replacement therapy (CRT) seeks to relieve both pathological and symptomatic PD manifestations, and has been shown to have beneficial effects in experimental PD models as well as in PD patients, but an apt cell line to be used in PD treatment has yet to be established. In addition, CRT clinical trials are more successful in younger PD patients with less advanced pathology. The main goal of this thesis was to study the effects of the transplantation of human neural stem cells (hNSCs), specifically hVM1 clone 32 cells, in an in vivo PD mouse model using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at four months post-transplant. The hypothesis was that the transplanted hNSCs could replace and take over the functions of the impaired or lost DAn by integrating in the host environment, thus rescuing nigrostriatal innervation, improving motor deficits, and exerting neurotrophic effects, in adult and middle-aged Parkinsonian mice. Transplantation of hVM1 clone 32 cells rescued dopaminergic nigrostriatal populations in adult Parkinsonian mice, plausibly via the neurotrophic factors released by the cells, indicating that conditioned media (CM) rather than cells could be sufficient in providing beneficial effects. There were no clear behavioral changes between groups except for reduced stride length and hyperactivity in all MPTP-treated mice, both of which tended to be improved by hVM1 clone 32 cell transplant in middle-aged mice, while hyperactivity had a tendency of decreasing in adult hNSC-transplanted mice. In adult mice, hNSC transplantation rescued neuroblast neurogenesis in the subgranular zone, which was correlated with dopaminergic recovery in the Str and SNpc. Neuroinflammation did not impede nigrostriatal system restoration in adult mice. In both age groups, grafting of hVM1 clone 32 cells led to mast cell migration to the superficial cervical lymph nodes. Therefore, this thesis is a proof-of-concept study that CRT can work using hVM1 clone 32 cells in adult Parkinsonian mice and that these hNSCs exert a trophic effect, but CRT is less effective in middle-aged mice due to the increased neuroinflammation and decreased neurogenesis that occur in aged animals. This study emphasizes the importance of the age of recipient and the stage of PD progression when receiving a transplant, and proposes that a multifactorial treatment is needed for CRT or CM infusion in older PD patients.