title: Endothelin-B Receptor Activation in Astrocytes Regulates the Rate of Oligodendrocyte Regeneration during Remyelination.
abstract: Reactive astrogliosis is an essential and ubiquitous response to CNS injury, but in some cases, aberrant activation of astrocytes and their release of inhibitory signaling molecules can impair endogenous neural repair processes. Our lab previously identified a secreted intercellular signaling molecule, called endothelin-1 (ET-1), which is expressed at high levels by reactive astrocytes in multiple sclerosis (MS) lesions and limits repair by delaying oligodendrocyte progenitor cell (OPC) maturation. However, as ET receptors are widely expressed on neural cells, the cell- and receptor-specific mechanisms of OPC inhibition by ET-1 action remain undefined. Using pharmacological approaches and cell-specific endothelin receptor (EDNR) ablation, we show that ET-1 acts selectively through EDNRB on astrocytes--and not OPCs--to indirectly inhibit remyelination. These results demonstrate that targeting specific pathways in reactive astrocytes represents a promising therapeutic target in diseases with extensive reactive astrogliosis, including MS.
authors.affiliation: Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Hammond
authors.affiliation: Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: McEllin
authors.affiliation: Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Morton
authors.affiliation: Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Raymond
authors.affiliation: Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Dupree
authors.affiliation: Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, DC 20010, USA. Electronic address: vgallo@cnmc.org.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Gallo
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D003711:Demyelinating Diseases / Q000378:metabolism*; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D046529:Microscopy, Electron, Transmission; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism*; D012038:Regeneration / Q000502:physiology
chemical_list: D019332:Endothelin-1; D044023:Receptor, Endothelin B