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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.

SUBMITTER: Hammond TR

PROVIDER: S-EPMC3935216 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Astrocyte-derived endothelin-1 inhibits remyelination through notch activation.

Hammond Timothy R TR Gadea Ana A Dupree Jeff J Kerninon Christophe C Nait-Oumesmar Brahim B Aguirre Adan A Gallo Vittorio V

Neuron 20140201 3

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. ...[more]

PMID: 24507193

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Project description:Astrocyte elevated gene-1 (AEG-1) and endothelin-1 (ET-1)/endothelin A receptor (ETAR) signaling have been demonstrated to be important in osteosarcoma (OS) progression. In the present study, we explored the interaction between AEG-1 and ET-1/ETAR signaling in OS cells, and investigated the mechanism(s) through which the functional interaction may impact OS cell invasion and chemoresistance. Overexpression and knockdown of AEG-1 were performed in Saos-2 and MG-63 OS cells, respectively. Overexpression of AEG-1 in Saos-2 cells significantly increased ET-1 expression (at both the mRNA and protein levels), cell invasion, MMP-2 expression and cell survival against cisplatin. These effects were eradicated using a selective phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, or a selective ETAR inhibitor, BQ123. Knockdown of AEG-1 in MG-63 cells significantly decreased ET-1 expression (at both the mRNA and protein levels), cell invasion, MMP-2 expression and cell survival against cisplatin. Exogenous ET-1 restored cell invasion and MMP-2 expression levels in MG-63 cells, in which AEG-1 had been knocked down, in the presence of LY294002, but not in the presence of BQ123. However, exogenous ET-1 only partially rescued cell survival against cisplatin-induced apoptosis in the presence of LY294002, in cells in which AEG-1 had been knocked down. In conclusion, we have demonstrated that AEG-1 regulates ET-1 expression at the transcriptional level in a PI3K-dependent manner in OS cells. Downstream of PI3K, ET-1/ETAR signaling primarily mediates the promoting effect of AEG-1 on OS cell invasion, likely through the upregulation of MMP-2 expression, thus, ET-1/ETAR signaling partially, but significantly, mediates the AEG-1-induced chemoresistance in OS cells. To the best of our knowledge, this study has provided the first evidence of a functional association between AEG-1 and ET-1/ETAR signaling in OS cells, which adds novel insights into the molecular mechanism of OS metastasis and chemoresistance.

Project description:The development of new regenerative therapies for multiple sclerosis is hindered by the lack of potential targets for enhancing remyelination. The study of naturally regenerative processes such as the innate immune response represents a powerful approach for target discovery to solve this problem. By 'mining' these processes using transcriptional profiling we can identify candidate factors that can then be tested individually in clinically-relevant models of demyelination and remyelination. Here, therefore, we have examined a previously described in vivo model of the innate immune response in which zymosan-induced macrophage activation in the retina promotes myelin sheath formation by oligodendrocytes generated from transplanted precursor cells. While this model is not itself clinically relevant, it does provide a logical starting point for this study as factors that promote myelination must be present. Microarray analysis of zymosan-treated retinae identified several cytokines (CXCL13, endothelin 2, CCL20 and CXCL2) to be significantly upregulated. When tested in a cerebellar slice culture model, CXCL13 and endothelin 2 promoted myelination and endothelin 2 also promoted remyelination. In studies to identify the receptor responsible for this regenerative effect of endothelin 2, analysis of both remyelination following experimental demyelination and of different stages of multiple sclerosis lesions in human post-mortem tissue revealed high levels of endothelin receptor type B in oligodendrocyte lineage cells. Confirming a role for this receptor in remyelination, small molecule agonists and antagonists of endothelin receptor type B administered in slice cultures promoted and inhibited remyelination, respectively. Antagonists of endothelin receptor type B also inhibited remyelination of experimentally-generated demyelination in vivo. Our work therefore identifies endothelin 2 and the endothelin receptor type B as a regenerative pathway and suggests that endothelin receptor type B agonists represent a promising therapeutic approach to promote myelin regeneration.

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Astrocyte-derived endothelin-1 inhibits remyelination through notch activation.

Publications

Astrocyte-derived endothelin-1 inhibits remyelination through notch activation.

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