Vitamin C-Induced Epigenetic Modifications in Donor NSCs Establish Midbrain Marker Expressions Critical For Cell-Based Therapy in Parkinson's Disease

Abstract

Cultured neural stem/precursor cells(NSCs) are regarded as a potential systematic cell source to treat Parkinson’s disease(PD). However, the therapeutic potential of these cultured NSCs is lost during culturing. Here, we show that vitamin C(VC) potentiates the therapeutic capacity of NSCs cultured from the ventral midbrain(VM), via enhancement of DA neuronal yield, survival, neuronal function, and midbrain-specific marker expression. VC acted by upregulating a series of midbrain DA neuron–specific developmental and phenotype genes via DNA hydroxymethylation/demethylation and repressive histone code (H3K9m3, H3K27m3) demethylation at associated gene promoter regions. Notably, the epigenetic changes induced by transient VC treatment were sustained long after VC withdrawal. Accordingly, transplantation of VC-treated NSCs resulted in remarkable behavioral improvement, along with enriched DA neuron engraftment, which faithfully expressed midbrain-specific markers in PD model rats. These results indicate that VC treatment to donor NSCs could be a simple, efficient, and safe therapeutic strategy for PD in the future.