title: Astrocyte-derived endothelin-1 inhibits remyelination through notch activation.
abstract: Oligodendrocyte progenitor cells (OPCs) can repair demyelinated lesions by maturing into myelin-producing oligodendrocytes. However, the OPC potential to differentiate can be prevented by inhibitory signals present in the pathological lesion environment. Identification of these signals is essential to promote OPC differentiation and lesion repair. We identified an endogenous inhibitor of remyelination, Endothelin-1 (ET-1), which is highly expressed in reactive astrocytes of demyelinated lesions. Using both gain- and loss-of-function approaches, we demonstrate that ET-1 drastically reduces the rate of remyelination. We also discovered that ET-1 acts mechanistically by promoting Notch activation in OPCs during remyelination through induction of Jagged1 expression in reactive astrocytes. Pharmacological inhibition of ET signaling prevented Notch activation in demyelinated lesions and accelerated remyelination. These findings reveal that ET-1 is a negative regulator of OPC differentiation and remyelination and is potentially a therapeutic target to promote lesion repair in demyelinated tissue.
authors: Center for Neuroscience Research, Children's National Medical Center, Washington, DC 20010, USA; Institute for Biomedical Sciences, The George Washington University, Washington, DC 20052, USA.
authors: Timothy R
authors: TR
authors: Hammond
authors: Center for Neuroscience Research, Children's National Medical Center, Washington, DC 20010, USA.
authors: Ana
authors: A
authors: Gadea
authors: Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA 23284, USA.
authors: Jeff
authors: J
authors: Dupree
authors: Centre de Recherche de l'Institut du Cerveauet de la Moelle Epinière, Inserm U.975; Université Pierre et Marie Curie-Paris 6 UMR-S975; CNRS UMR 7225; and AP-HP Groupe Hospitalier Pitié-Salpêtrière, Fédération de Neurologie, Cedex 13, Paris, France.
authors: Christophe
authors: C
authors: Kerninon
authors: Centre de Recherche de l'Institut du Cerveauet de la Moelle Epinière, Inserm U.975; Université Pierre et Marie Curie-Paris 6 UMR-S975; CNRS UMR 7225; and AP-HP Groupe Hospitalier Pitié-Salpêtrière, Fédération de Neurologie, Cedex 13, Paris, France.
authors: Brahim
authors: B
authors: Nait-Oumesmar
authors: Pharmacological Sciences Department, SUNY at Stony Brook University, Stony Brook, NY 11794, USA.
authors: Adan
authors: A
authors: Aguirre
authors: Center for Neuroscience Research, Children's National Medical Center, Washington, DC 20010, USA; Institute for Biomedical Sciences, The George Washington University, Washington, DC 20052, USA. Electronic address: vgallo@cnmcresearch.org.
authors: Vittorio
authors: V
authors: Gallo
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D019332:Endothelin-1 / Q000009:adverse effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009842:Oligopeptides / Q000494:pharmacology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology
chemical_list: D002135:Calcium-Binding Proteins; D019332:Endothelin-1; D005904:Glial Fibrillary Acidic Protein; D036341:Intercellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D009842:Oligopeptides; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; C076213:PD 142893; D049452:Green Fluorescent Proteins