Astrocyte-derived endothelin-1 inhibits remyelination through notch activation

Timothy R Hammond; Ana Gadea; Jeff Dupree; Christophe Kerninon; Brahim Nait-Oumesmar; Adan Aguirre; Vittorio Gallo

doi:10.1016/j.neuron.2013.11.015

Astrocyte-derived endothelin-1 inhibits remyelination through notch activation

Neuron. 2014 Feb 5;81(3):588-602. doi: 10.1016/j.neuron.2013.11.015.

Authors

Timothy R Hammond¹, Ana Gadea², Jeff Dupree³, Christophe Kerninon⁴, Brahim Nait-Oumesmar⁴, Adan Aguirre⁵, Vittorio Gallo⁶

Affiliations

¹ 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.
² Center for Neuroscience Research, Children's National Medical Center, Washington, DC 20010, USA.
³ Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA 23284, USA.
⁴ 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.
⁵ Pharmacological Sciences Department, SUNY at Stony Brook University, Stony Brook, NY 11794, USA.
⁶ 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: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Astrocytes / drug effects
Astrocytes / metabolism*
Astrocytes / ultrastructure
Calcium-Binding Proteins / metabolism
Cell Count
Cell Differentiation / drug effects
Demyelinating Diseases / chemically induced
Demyelinating Diseases / drug therapy
Demyelinating Diseases / metabolism
Demyelinating Diseases / pathology*
Disease Models, Animal
Drug Delivery Systems
Endothelin-1 / adverse effects
Endothelin-1 / metabolism*
Gene Expression Regulation / drug effects
Gene Expression Regulation / genetics
Gene Expression Regulation / physiology*
Glial Fibrillary Acidic Protein / genetics
Green Fluorescent Proteins / genetics
Intercellular Signaling Peptides and Proteins / metabolism
Jagged-1 Protein
Lipopolysaccharides / pharmacology
Membrane Proteins / metabolism
Mice
Mice, Inbred C57BL
Mice, Transgenic
Oligopeptides / pharmacology
Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
Receptors, Notch / metabolism*
Serrate-Jagged Proteins
Stem Cells / drug effects
Stem Cells / physiology

Substances

Calcium-Binding Proteins
Endothelin-1
Glial Fibrillary Acidic Protein
Intercellular Signaling Peptides and Proteins
Jag1 protein, mouse
Jagged-1 Protein
Lipopolysaccharides
Membrane Proteins
Oligopeptides
Platelet Endothelial Cell Adhesion Molecule-1
Receptors, Notch
Serrate-Jagged Proteins
PD 142893
Green Fluorescent Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding