Damage to the myelin sheath (demyelination) in multiple sclerosis (MS) retards the propagation of nerve impulses, with devastating neurological consequences. Remyelination restores myelin through the proliferation, migration and maturation of oligodendrocyte (OL) progenitor cells (OPCs). The failure of remyelination by OPCs in MS lesions is not understood, and the identification of inhibitory factors in lesions is critical to improve repair. Demyelination results in reactive gliosis, an astrocytic response that impedes OL development and regeneration. Strategies that target inhibitory factors of reactive gliosis could improve remyelination by OPCs. We have shown that: i) Endothelin-1 (ET-1) is expressed at high levels by reactive astrocytes in MS lesions; ii) in an animal model of demyelination, astrocyte-derived ET-1 delays OPC differentiation and remyelination, and iii) inhibition of ET-1 signaling accelerates myelin repair. ETA- and ETB-receptors (ET-Rs) are expressed by astrocytes and OPCs, but the specific contribution of each receptor and each cell type to the remyelination phenotype is unknown. Our preliminary data show that pharmacological inhibition of ETB-Rs or selective ETB-R deletion in astrocytes accelerates remyelination, suggesting a major functional role for this ET-R subtype. We will use two novel conditional knock-out mouse strains, hGFAP-Cre ;ETBflox/flox and PDGF a- R ERT2 Cre ;ETBflox/flox, in which the ETB-R is inducibly ablated in astrocytes or OPCs. We will test the ERT2 hypothesis that ET-1 acts predominantly through the ETB-R on astrocytes to inhibit remyelination. We will determine: i) the functional role of ET-Rs in remyelination and determine whether the ETB-R is the predominant functional receptor involved in this process; ii) the specific role of ETB-R signaling on astrocytes during remyelination; iii) the specific role of ETB-R signaling on OPCs during remyelination, and iv) whether the inhibitory effects of ET-1 on OPCs and remyelination are direct or mediated by astrocytes. Our studies will provide crucial insight into the mechanisms by which ET-1 limits remyelination, and will identify new potential therapeutic targets to promote OL regeneration and myelin repair in demyelinating diseases.
Demyelination in the central nervous system results in reactive gliosis, an astrocytic response that adversely affects neuronal and oligodendrocyte survival, axonal regeneration and remyelination. We have shown that Endothelin-1 (ET-1) is an astrocyte signal that regulates reactive gliosis and prevents oligodendrocyte progenitor cell differentiation after demyelination through activation of the Notch pathway. We will identify the direct and indirect cellular targets of ET-1, and identify the receptor that mediates the effects o this peptide on remyelination efficiency.
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| Hammond, Timothy R; McEllin, Brian; Morton, Paul D et al. (2015) Endothelin-B Receptor Activation in Astrocytes Regulates the Rate of Oligodendrocyte Regeneration during Remyelination. Cell Rep 13:2090-7 |
