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Fibrinogen Activates BMP Signaling in Oligodendrocyte Progenitor Cells and Inhibits Remyelination after Vascular Damage.
Neuron ( IF 16.2 ) Pub Date : 2017-Dec-06 , DOI: 10.1016/j.neuron.2017.10.008
Mark A Petersen 1 , Jae Kyu Ryu 2 , Kae-Jiun Chang 3 , Ainhoa Etxeberria 3 , Sophia Bardehle 2 , Andrew S Mendiola 2 , Wanjiru Kamau-Devers 4 , Stephen P J Fancy 5 , Andrea Thor 6 , Eric A Bushong 6 , Bernat Baeza-Raja 2 , Catriona A Syme 2 , Michael D Wu 7 , Pamela E Rios Coronado 2 , Anke Meyer-Franke 2 , Stephanie Yahn 8 , Lauriane Pous 9 , Jae K Lee 8 , Christian Schachtrup 10 , Hans Lassmann 11 , Eric J Huang 12 , May H Han 13 , Martina Absinta 14 , Daniel S Reich 14 , Mark H Ellisman 15 , David H Rowitch 16 , Jonah R Chan 3 , Katerina Akassoglou 17
Affiliation  

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 fate in 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 remyelination in 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:

纤维蛋白原激活少突胶质细胞祖细胞中的 BMP 信号传导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进入 CNS 来改变大脑微环境的组成。然而,血液衍生分子是否可作为髓鞘再生的外在抑制剂尚不清楚。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 (OPCs) 中的骨形态发生蛋白 (BMP) 信号通路并抑制髓鞘再生。纤维蛋白原诱导 Smad 1/5/8 的磷酸化并抑制 OPC 分化为有髓鞘少突胶质细胞 (OLs),同时在体外促进星形胶质细胞的命运。纤维蛋白原效应通过在 OPCs 中使用 dorsomorphin 同源物 1 (DMH1) 或 CRISPR/Cas9 激活素 A 受体 I 型 (ACVR1) 敲除来抑制 BMP I 型受体来挽救。脱髓鞘多发性硬化 (MS) 病变中的纤维蛋白原和 BMP 靶标 Id2 增加。纤维蛋白原的治疗性消耗降低了 BMP 信号传导并增强了体内的髓鞘再生。靶向纤维蛋白原可能是促进 CNS 祖细胞在髓鞘再生失败疾病中的再生潜力的上游治疗策略。
更新日期:2017-11-02
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