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 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in C57BL/6 mice. 2.5x105 GFP-labeled Er-NPCs were infused unilaterally by stereotaxic injection in the left striatum. Functional recovery was assessed by two independent behavioral tests. The potential effects of Er-NPCs on neuroinflammation was assessed by measuring the expression of pro-inflammatory and anti-inflammatory cytokines and evaluating by immunohistochemistry approach the expression of specific markers. The fate of transplanted cells was also investigated. Our results show that animals grafted with Er-NPCs present a remarkable behavioral improvement beginning the third day after transplantation and increasing in the following observational period. Engrafted Er-NPCs are vital, do not form tumors, and migrate ventrally and caudally from the injection site within the striatum, reaching the Substantia Nigra pars compacta. Furthermore, Er-NPCs administration promotes a rapid anti-inflammatory effect that was already evident 24h after transplant, with a decreased expression of pro-inflammatory cytokines (IL-1alpha, 1beta, IL6, TNF-alpha) and an increased expression of anti-inflammatory cytokines such as IL10. Er-NPCs transplant also reduces macrophages infiltration, directly counteracting the M1 pro-inflammatory response of primary murine activated microglia and inducing M2 pro-regeneration traits. Moreover, we show that erythropoietin, 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.