Blood-brain barrier (BBB) disruption alters the composition of the brain microenvironment by allowing blood proteins into the CNS. However, whether blood-derived molecules serve as extrinsic inhibitors of remyelination is unknown. Here we show that the coagulation factor fibrinogen activates the bone morphogenetic protein (BMP) signaling pathway in oligodendrocyte progenitor cells (OPCs) and suppresses remyelination. Fibrinogen induces phosphorylation of Smad 1/5/8 and inhibits OPC differentiation into myelinating oligodendrocytes (OLs) while promoting an astrocytic fatein vitro. Fibrinogen effects are rescued by BMP type I receptor inhibition using dorsomorphin homolog 1 (DMH1) or CRISPR/Cas9 activin A receptor type I (ACVR1) knockout in OPCs. Fibrinogen and the BMP target Id2 are increased in demyelinated multiple sclerosis (MS) lesions. Therapeutic depletion of fibrinogen decreases BMP signaling and enhances remyelinationin vivo. Targeting fibrinogen may be an upstream therapeutic strategy to promote the regenerative potential of CNS progenitors in diseases with remyelination failure.

中文翻译：

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纤维蛋白原激活少突胶质祖细胞中的BMP信号并抑制血管损伤后的髓鞘再生。

血脑屏障（BBB）破坏通过允许血液蛋白质进入中枢神经系统来改变大脑微环境的组成。然而，尚不清楚血液来源的分子是否充当髓鞘再生的外在抑制剂。在这里，我们显示凝血因子纤维蛋白原激活少突胶质祖细胞（OPC）中的骨形态发生蛋白（BMP）信号传导途径并抑制髓鞘再生。纤维蛋白原诱导Smad 1/5/8的磷酸化并抑制OPC分化为髓鞘少突胶质细胞（OLs），同时促进体外星形胶质细胞的命运。可以通过在OPC中使用dorsomorphin同系物1（DMH1）或CRISPR / Cas9激活素A受体I型（ACVR1）敲除BMP I类受体来挽救纤维蛋白原的作用。纤维蛋白原和BMP目标Id2在脱髓鞘多发性硬化症（MS）病变中增加。纤维蛋白原的治疗耗竭可降低BMP信号传导并增强体内的髓鞘再生。靶向纤维蛋白原可能是一种上游治疗策略，可促进中枢神经系统祖细胞在髓鞘再生失败的疾病中具有再生潜力。