Conforti Pasquale, Mezey Szilvia, Nath Suvra, Chu Yu-Hsuan, Malik Subash C, Martínez Santamaría Jose C, Deshpande Sachin S, Pous Lauriane, Zieger Barbara, Schachtrup Christian
Faculty of Medicine, Institute of Anatomy and Cell Biology, University of Freiburg, Freiburg, Germany.
Faculty of Biology, University of Freiburg, Freiburg, Germany.
Glia. 2022 Jul;70(7):1251-1266. doi: 10.1002/glia.24166. Epub 2022 Mar 4.
Reactive astrocytes at the border of damaged neuronal tissue organize into a barrier surrounding the fibrotic lesion core, separating this central region of inflammation and fibrosis from healthy tissue. Astrocytes are essential to form the border and for wound repair but interfere with neuronal regeneration. However, the mechanisms driving these astrocytes during central nervous system (CNS) disease are unknown. Here we show that blood-derived fibrinogen is enriched at the interface of lesion border-forming elongated astrocytes after cortical brain injury. Anticoagulant treatment depleting fibrinogen reduces astrocyte reactivity, extracellular matrix deposition and inflammation with no change in the spread of inflammation, whereas inhibiting fibrinogen conversion into fibrin did not significantly alter astrocyte reactivity, but changed the deposition of astrocyte extracellular matrix. RNA sequencing of fluorescence-activated cell sorting-isolated astrocytes of fibrinogen-depleted mice after cortical injury revealed repressed gene expression signatures associated with astrocyte reactivity, extracellular matrix deposition and immune-response regulation, as well as increased gene expression signatures associated with astrocyte metabolism and astrocyte-neuron communication. Systemic pharmacologic depletion of fibrinogen resulted in the absence of elongated, border-forming astrocytes and increased the survival of neurons in the lesion core after cortical injury. These results identify fibrinogen as a critical trigger for lesion border-forming astrocyte properties in CNS disease.
受损神经元组织边界处的反应性星形胶质细胞会组织形成围绕纤维化病变核心的屏障，将炎症和纤维化的中央区域与健康组织分隔开来。星形胶质细胞对于形成边界和伤口修复至关重要，但会干扰神经元再生。然而，在中枢神经系统（CNS）疾病期间驱动这些星形胶质细胞的机制尚不清楚。在这里，我们表明，脑皮质损伤后，血液来源的纤维蛋白原在形成病变边界的伸长星形胶质细胞的界面处富集。消耗纤维蛋白原的抗凝治疗可降低星形胶质细胞反应性、细胞外基质沉积和炎症，而炎症扩散无变化，而抑制纤维蛋白原转化为纤维蛋白并未显著改变星形胶质细胞反应性，但改变了星形胶质细胞细胞外基质的沉积。对脑皮质损伤后纤维蛋白原耗尽小鼠的荧光激活细胞分选分离的星形胶质细胞进行RNA测序，揭示了与星形胶质细胞反应性、细胞外基质沉积和免疫反应调节相关的基因表达特征受到抑制，以及与星形胶质细胞代谢和星形胶质细胞 - 神经元通讯相关的基因表达特征增加。全身性纤维蛋白原药理学消耗导致在脑皮质损伤后缺乏伸长的、形成边界的星形胶质细胞，并增加了病变核心中神经元的存活率。这些结果确定纤维蛋白原为中枢神经系统疾病中形成病变边界的星形胶质细胞特性的关键触发因素。
