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.


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


  • 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