English Version: http://www.medicaldaily.com/potentia...-damage-268918
This particular study, published in Neuron, pinpointed the protein known as Endothelin-1, or ET-1, as having therapeutic potential; it could repair tissue, as it has been shown to inhibit repair of myelin. Targeting ET-1 would involve identifying signals in cells that promote lesion repair.
Medical Term Version: http://www.cell.com/neuron/retrieve/...96627313010830
Highlights
Summary
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.
This particular study, published in Neuron, pinpointed the protein known as Endothelin-1, or ET-1, as having therapeutic potential; it could repair tissue, as it has been shown to inhibit repair of myelin. Targeting ET-1 would involve identifying signals in cells that promote lesion repair.
Medical Term Version: http://www.cell.com/neuron/retrieve/...96627313010830
Highlights
- ET-1 is highly upregulated in astrocytes in human MS lesions
- Astrocyte-derived ET-1 inhibits remyelination
- ET-1 is an endogenous regulator of Notch signaling
- ET-R antagonist PD142,893 can be used therapeutically to promote remyelination
Summary
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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