HB-EGF and EGF infusion following CNS demyelination mitigates age-related decline in regeneration of oligodendrocytes from neural precursor cells originating in the ventricular-subventricular zone

Abstract

In multiple sclerosis (MS), chronic demyelination initiated by immune-mediated destruction of myelin, leads to axonal damage and neuronal cell death, resulting in a progressive decline in neurological function. The development of interventions that potentiate remyelination could hold promise as a novel treatment strategy for MS. To this end, our group has demonstrated that neural precursor cells (NPCs) residing in the ventricular-subventricular zone (V-SVZ) of the adult mouse brain contribute significantly to remyelination in response to central nervous system (CNS) demyelination and can regenerate myelin of normal thickness. However, aging takes its toll on the regenerative potential of NPCs and reduces their contribution to remyelination. In this study, we investigated how aging influences the contribution of NPCs to oligodendrogenesis during the remyelination process and whether the delivery of growth factors into the brains of aged mice could potentiate the oligodendrogenic potential of NPCs. To enable us to map the fate of NPCs in response to demyelination induced at different postnatal ages, Nestin-CreERT2; Rosa26-LSL-eYFP mice were gavaged with tamoxifen at either 8 weeks, 30 weeks or one year of age before being challenged with cuprizone for a period of six weeks. Using osmotic minipumps, we infused heparin-binding EGF-like growth factor (HB-EGF), and/or epidermal growth factor (EGF) into the cisterna magna for a period of two weeks beginning at the peak of cuprizone-induced demyelination (n=6-8 mice per group). Control mice received artificial cerebrospinal fluid (vehicle) alone. Mice were perfused six weeks after cuprizone withdrawal and the contribution of NPCs to oligodendrocyte regeneration in the corpus callosum was assessed. Our data reveal that although NPC-derived oligodendrocyte generation declined dramatically with age, this decline was partially reversed by growth factor infusion. Notably, co-infusion of EGF and HB-EGF increased oligodendrocyte regeneration twofold in some regions of the corpus callosum. Our results shed light on the beneficial effects of EGF and HB-EGF for increasing the contribution of NPCs to remyelination and indicate their therapeutic potential to combat the negative effects of aging upon remyelination efficacy.