Astrocyte-derived endothelin-1 inhibits remyelination through notch activation
Open accessAbstract
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.
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LPC-induced demyelination reproduces many features of demyelinated lesions in MS patients.
“LPC-induced demyelination is frequently used to study myelin repair and recapitulates many aspects of the demyelinated lesions found in patients with multiple sclerosis (MS) (Hammond et al., 2014).”
From Complex cell-state changes revealed by single cell RNA sequencing of 76,149 microglia throughout the mouse lifespan and in the injured brain (2018) · cites this paper as Hammond et al., 2014
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- Authors
- Hammond, T. R., Gadea, A., Dupree, J., Kerninon, C., Nait-Oumesmar, B., Aguirre, A., & Gallo, V.
- Affiliations
- Children's National (US)
- Centre National de la Recherche Scientifique (FR)
- Stony Brook University (US)
- Corresponding author
- Gallo, Vittorio
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2014-02
- Volume
- 81
- Issue
- 3
- Pages
- 588-602
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC3935216
- OpenAlex
- W1998475020
- Cited by
- 206
- References
- 55
- Citations by year
- 2026: 12 · 2025: 11 · 2024: 13 · 2023: 12 · 2022: 19 · 2021: 15 · 2020: 28 · 2019: 25 · 2018: 11 · 2017: 21 · 2016: 17 · 2015: 18 · 2014: 4
- FWCI
- 14.76
- Type
- journal article
- Language
- en
- Update notices
- erratum (2014-03-19)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- George Washington University
- National Institute of Neurological Disorders and Stroke (R00NS057944, R01NS045702, R01NS056427)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD040677)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Spinal Cord Injury Research
- Keywords
- endothelin-1, remyelination, oligodendrocyte precursor cells, Notch signaling, reactive astrocytes, Jagged1, demyelination, oligodendrocyte differentiation, demyelinating lesions, therapeutic target
- MeSH terms
- Serrate-Jagged Proteins, Jagged-1 Protein, Animals, Astrocytes, Calcium-Binding Proteins, Cell Count, Cell Differentiation, Demyelinating Diseases, Disease Models, Animal, Gene Expression Regulation, Glial Fibrillary Acidic Protein, Lipopolysaccharides, Membrane Proteins, Mice, Inbred C57BL, Mice, Transgenic, Oligopeptides, Stem Cells, Drug Delivery Systems, Endothelin-1, Platelet Endothelial Cell Adhesion Molecule-1, Intercellular Signaling Peptides and Proteins, Green Fluorescent Proteins, Mice, Receptors, Notch
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