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首页> 外文期刊>Neuron >Astrocyte-Derived Endothelin-1 Inhibits Remyelination through Notch Activation
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Astrocyte-Derived Endothelin-1 Inhibits Remyelination through Notch Activation

机译：星形胶质细胞内皮素-1通过Notch激活抑制髓鞘再生。

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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 anegative regulator of OPC differentiation and remyelination and is potentially a therapeutic target to promote lesion repair in demyelinated tissue.
机译：少突胶质细胞祖细胞（OPC）可以通过成熟进入产生髓磷脂的少突胶质细胞来修复脱髓鞘的病变。但是，OPC分化的潜力可以通过病理病变环境中存在的抑制信号来预防。这些信号的识别对于促进OPC分化和病变修复至关重要。我们确定了一种内源性的髓鞘再生抑制剂内皮素-1（ET-1），其在脱髓鞘病变的反应性星形胶质细胞中高度表达。使用功能获得和功能丧失方法，我们证明ET-1大大降低了髓鞘再生速率。我们还发现，ET-1通过在髓鞘再生过程中通过诱导星形胶质细胞中Jagged1表达的诱导来促进OPC中的Notch活化而发挥机械作用。 ET信号传导的药理学抑制作用阻止了脱髓鞘病变中的Notch活化并加速了髓鞘再生。这些发现表明，ET-1是OPC分化和髓鞘再生的负性调节剂，并且可能是促进脱髓鞘组织中病变修复的治疗靶标。

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