New CNS neurons and glia are generated throughout adulthood from endogenous neural stem and progenitor cells. These progenitors can respond to injury, but their ability to proliferate, migrate, differentiate, and survive is usually insufficient to replace lost cells and restore normal function. Potentiating the progenitor response with exogenous factors is an attractive strategy for the treatment of nervous system injuries and neurodegenerative and demyelinating disorders. Previously, we reported that delivery of Leukemia inhibitory factor (LIF) to the CNS stimulates the self-renewal of neural stem cells and the proliferation of parenchymal glial progenitors. Here we identify these parenchymal glia as oligodendrocyte (OL) progenitor cells (OPCs) and show that LIF delivery stimulates their proliferation through the activation of gp130 receptor signaling within these cells. Importantly, this effect of LIF on OPC proliferation can be harnessed to enhance the generation of OLs that express myelin proteins and reform nodes of Ranvier in the context of chronic demyelination in the adult mouse hippocampus. Our findings, considered together with the known beneficial effects of LIF on OL and neuron survival, suggest that LIF has both reparative and protective activities that make it a promising potential therapy for CNS demyelinating disorders and injuries.
Although I do not tend to discuss animal studies too much as it is abit sceince fiction and a long way from the clinic, but I know you are particulalrly interested in repair, so I serve up some new research that reports on another avenue to promote remyelination.
In multiple sclerosis (MS), chronic demyelination leads to axonal damage. Although oligodendrocyte precursors (cells that mature to become cells that make myelin) proliferate, differentiate, mature, and remyelinate axons in adult brains, this happens too slowly to compensate for the loss in MS. Stimulating endogenous processes might be an effective means to treat the disease, however. Leukemia inhibitory factor (LIF) stimulates oligodendrocyte precursor cell (OPC) proliferation, oligodendrocyte maturation, and myelination in cultures, and as shown here it produces similar effects in living animals. Injection into the brain of adenovirus expressing LIF (Ad-LIF) increased OPC proliferation in mice. Furthermore, after cuprizone (a chemical poison of oligodendrocytes)-induced demyelination, Ad-LIF greatly increased the number of mature oligodendrocytes and the extent of myelination in the hippocampus. Interestingly, some remyelination does not depend on LIF: enhanced proliferation and maturation were not detected in white matter tracts that underwent extensive spontaneous remyelination after cuprizone treatment, and inactivating the LIF receptor blocked the effects of Ad-LIF without affecting spontaneous recovery.
However, let us not get too carried away ye, as we will have to determine whether adenoviral vectors are a real way to deliver the LIF. Historically adenoviral vectors have been great at producing lots of proteins encoded by the viral vectors, but they have been immunogenic and so the immune system has got rid of them and presumably the cells expressing the virus after a short while. Whilst the new generation adenoviral vectors are less likely to stimulate the immune response this can still be a problem. So maybe we need to find other ways to stimulate the LIF receptor to promote remyelination.