Neural Stem Cells transplantation in pre-clinical experimental model of Parkinson’s: counteraction of neuroinflammation and promotion of functional recovery

Parkinson's disease (PD) is the second most common neurodegenerative disease, caused by midbrain dopaminergic neurons degeneration. Cell therapies have long been considered a feasible regenerative approach to compensate for cellular loss. Erythropoietin-releasing Neural Precursors (Er-NPCs) are a subclass of SVZ-derived neural progenitors with high neural differentiation features and able to survive in an unfavorable microenvironment. The aim of this work was to investigate the therapeutic potential of Er-NPCs in pre-clinical experimental model of PD, obtained by the intraperitoneal administration of MPTP in C57BL/6 mice. 2.5x105 GFP-Er-NPCs were infused by stereotaxic injection in the mice left striatum. Functional recovery was assessed by two behavioral tests. The effects of Er-NPCs on neuroinflammation was assessed by measuring the expression of pro- and anti-inflammatory cytokines and evaluating by immunohistochemistry approach the expression of specific markers. Our results show that animals grafted with Er-NPCs present a behavioral improvement beginning the day 3 after transplantation and increasing in the observational period. Engrafted Er-NPCs are vital, do not form tumors, and migrate from the injection site within the striatum, reaching the SN. Furthermore, Er-NPCs administration promotes anti-inflammatory effect that was evident 24h after transplant, with a decreased expression of IL-1α, 1β, IL6, TNFα and an increased expression of IL10. Er-NPCs transplant also reduces macrophages infiltration, counteracting the M1 pro-inflammatory response the activated microglia and inducing M2 pro-regeneration traits. Moreover, we show that EPO, physiologically released by Er-NPCs, mediates these activities, since the co-injection of precursors with anti-EPO/EPOR antibodies neutralizes the effect of the treatment. We suggest that Er-NPCs represent good candidates for cellular therapy in PD for their differentiation capabilities and their anti-inflammatory properties.