The Journal of Neuroscience is the official journal of the Society for Neuroscience. The Journal publishes papers on a broad range of topics of general interest to those working on the nervous system.
Exogenous Leukemia Inhibitory Factor Stimulates Oligodendrocyte Progenitor Cell Proliferation and Enhances Hippocampal Remyelination
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.
Benjamin E. Deverman and Paul H. Patterson
(see current issue pages 2100–2109)
In traumatic brain injury and multiple sclerosis (MS), chronic demyelination leads to axonal damage. Although oligodendrocyte precursors 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 Deverman and Patterson show that it produces similar effects in vivo. Intracerebroventricular injection of adenovirus expressing LIF (Ad-LIF) increased OPC proliferation in mice.
Furthermore, after cuprizone-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.