Fibrinogen triggers astrocyte scar formation by promoting the availability of active TGF-beta after vascular damage.
Fibrinogen triggers astrocyte scar formation by promoting the availability of active TGF-beta after vascular damage.
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DOI：
10.1523/jneurosci.0137-10.2010
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发表时间：
2010-04-28
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影响因子：
--
通讯作者：
Akassoglou K
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文献类型：
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作者：
Schachtrup C;Ryu JK;Helmrick MJ;Vagena E;Galanakis DK;Degen JL;Margolis RU;Akassoglou K
神经系统中的疤痕形成在创伤后数小时内开始，其主要特征是反应性星形胶质细胞沉积抑制再生的蛋白多糖。中枢神经系统修复的一个基本问题是触发神经胶质疤痕形成的初始分子介质的身份。在这里，我们发现血液蛋白纤维蛋白原在血脑屏障（BBB）破坏或血管损伤后立即渗入中枢神经系统，作为通过 TGF-β/Smad 信号通路诱导神经胶质疤痕形成的早期信号。我们的研究表明，纤维蛋白原是潜在 TGF-β 的载体，可诱导星形胶质细胞中 Smad2 的磷酸化，从而抑制神经突生长。与这些发现一致的是，小鼠中纤维蛋白原的遗传或药理消耗减少了皮质损伤后的活性 TGF-β、Smad2 磷酸化、神经胶质细胞活化和神经胶质细胞沉积。此外，将纤维蛋白原立体定向注射到小鼠皮质中足以诱导星形胶质细胞增生。抑制 TGF-β 受体途径可以消除纤维蛋白原诱导的体内和体外神经胶质疤痕形成的影响。这些结果将纤维蛋白原确定为主要的星形胶质细胞激活信号，提供了证据表明抑制性蛋白聚糖的沉积是由血管破裂后中枢神经系统中渗漏的血液蛋白诱导的，并指出 TGF-β 是血管通透性和疤痕形成之间的分子联系。
Scar formation in the nervous system begins within hours after traumatic injury and is characterized primarily by reactive astrocytes depositing proteoglycans that inhibit regeneration. A fundamental question in CNS repair has been the identity of the initial molecular mediator that triggers glial scar formation. Here we show that the blood protein fibrinogen, which leaks into the CNS immediately after blood-brain barrier (BBB) disruption or vascular damage, serves as an early signal for the induction of glial scar formation via the TGF-β/Smad signaling pathway. Our studies revealed that fibrinogen is a carrier of latent TGF-β and induces phosphorylation of Smad2 in astrocytes that leads to inhibition of neurite outgrowth. Consistent with these findings, genetic or pharmacologic depletion of fibrinogen in mice reduces active TGF-β, Smad2 phosphorylation, glial cell activation and neurocan deposition following cortical injury. Furthermore, stereotactic injection of fibrinogen into the mouse cortex is sufficient to induce astrogliosis. Inhibition of the TGF-β receptor pathway abolishes the fibrinogen-induced effects on glial scar formation in vivo and in vitro. These results identify fibrinogen as a primary astrocyte activation signal, provide evidence that deposition of inhibitory proteoglycans is induced by a blood protein that leaks in the CNS after vasculature rupture, and point to TGF-β as a molecular link between vascular permeability and scar formation.