Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, California 94158, USA.
J Neurosci. 2010 Apr 28;30(17):5843-54. doi: 10.1523/JNEUROSCI.0137-10.2010.
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-beta/Smad signaling pathway. Our studies revealed that fibrinogen is a carrier of latent TGF-beta 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-beta, Smad2 phosphorylation, glial cell activation, and neurocan deposition after cortical injury. Furthermore, stereotactic injection of fibrinogen into the mouse cortex is sufficient to induce astrogliosis. Inhibition of the TGF-beta 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-beta as a molecular link between vascular permeability and scar formation.
神经系统中的瘢痕形成始于创伤后数小时内，其主要特征是反应性星形胶质细胞沉积蛋白聚糖，从而抑制再生。中枢神经系统修复的一个基本问题是引发神经胶质瘢痕形成的初始分子介质的身份。在这里，我们表明，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，通过 TGF-β/Smad 信号通路充当诱导神经胶质瘢痕形成的早期信号。我们的研究表明，纤维蛋白原是潜伏 TGF-β的载体，并诱导星形胶质细胞中 Smad2 的磷酸化，从而抑制神经突生长。这些发现与以下发现一致：在小鼠中基因敲除或药物耗竭纤维蛋白原可减少活性 TGF-β、Smad2 磷酸化、神经胶质细胞激活和皮质损伤后的神经粘蛋白沉积。此外，将纤维蛋白原立体定向注射到小鼠皮层中足以诱导星形胶质细胞增生。抑制 TGF-β受体途径可消除纤维蛋白原在体内和体外对神经胶质瘢痕形成的影响。这些结果将纤维蛋白原鉴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渗入中枢神经系统的血液蛋白诱导的，并指出 TGF-β是血管通透性和瘢痕形成之间的分子联系。
