Multiple sclerosis (MS) is a disease of the central nervous system characterized by relapsing-remitting episodes of inflammation and demyelination that result in axonal damage and eventually axonal loss. Current therapies cannot prevent or restore axonal damage since they do not promote rapid remyelination of affected axons. Implantation of myelinating cells could be an efficient strategy for that. Neural stem cells (NSCs) and NSC-derived oligodendrocyte precursor cells (OPCs) are considered a promising clinically relevant source for such remyelinating cell grafts provided that (a) they can be stably differentiated into oligodendrocyte precursor cells (OPCs) and (b) maturate into long-term functional oligodendrocytes after implantation. Therefore, our research focused on (a) revealing regulatory mechanisms that underlie the differentiation of NSCs into OPCs and (b) monitoring the survival, migration, and functionality of NSC-derived OPCs after implantation in MS animal models. We showed the indispensable role of the epigenetic regulator polycomb group protein Ezh2 in the stable differentiation of NSCs into OPCs and, by using high throughput DNA sequencing, we were able to pinpoint the specific genes whose expression is controlled by Ezh2 during NSC selfrenewal and OPC-differentiation. Using bioluminescence imaging, validated by immunohistochemical and electron microscopic analysis, we were able to monitor the fate of NSC-derived OPCs after grafting in MS models; we demonstrated their long-term ability to remyelinate axons and their efficacy to reduce clinical symptoms in acute as well as chronic EAE. Our data provide novel insight in the mechanism of oligodendrocyte differentiation and pave the way towards the clinical application of autologous NSC-derived OPCs in MS patients.
