Sox2-dependent fibronectin fibrillogenesis controls directional collective migration of Schwann cells

The extracellular matrix is essential for tissue formation and regeneration through the control of cellular behavior. Deregulation of extracellular matrix components is associated to disease, including neurodegeneration. After peripheral nerve injury, Schwann cells guide regrowing axons to their targets. These glial cells migrate collectively and provide an extracellular environment to enable neural repair. How this occurs remains poorly understood. Here, we show that Sox2 controls fibronectin fibrillogenesis in Schwann cells to provide a highly oriented extracellular matrix, which supports their rapid collective migration with a continuous cellular flow. Sox2 directly activates fibronectin expression in Schwann cells, leading to an increase in fibrillogenesis and cellular huddling. Accordingly, loss of fibrillogenesis leads to glial disassembly and disorganized axon regrowth. In vivo, 7 days post nerve injury, we found that pro-regenerative Schwann cells co-express Sox2 and the EIIIA-containing fibronectin splicing isoform. This mechanism is conserved in mammals, including humans, but absent in zebrafish. Taken together, our results demonstrate that Sox2 directly controls fibrillogenesis and provide a novel mechanism for the modification of the environmental architecture by glial cells during neuronal repair.细胞外基质（extracellular matrix）通过调控细胞行为，在组织形成与再生过程中发挥核心作用。细胞外基质组分失调与多种疾病密切相关，其中包括神经退行性病变。当发生周围神经损伤时，雪旺细胞（Schwann cells）会引导再生轴突靶向至损伤部位。这类神经胶质细胞可通过集体迁移构建适宜的细胞外微环境，以促进神经修复，但其具体分子机制至今尚未明确。 本研究证实，雪旺细胞中的Sox2可调控纤连蛋白纤维形成（fibronectin fibrillogenesis），进而形成高度取向的细胞外基质，支持雪旺细胞借助持续的细胞流实现快速集体迁移。Sox2可直接激活雪旺细胞内的纤连蛋白表达，从而增强纤连蛋白纤维形成与细胞簇集。反之，纤连蛋白纤维形成受损会导致胶质细胞解体以及轴突再生紊乱。 在体实验结果显示，神经损伤7天后，促再生型雪旺细胞共表达Sox2与含EIIIA结构域的纤连蛋白剪接变异体。该调控机制在包括人类在内的哺乳动物中保守存在，但在斑马鱼中并未发现。 综上，本研究结果表明Sox2可直接调控纤连蛋白纤维形成，揭示了神经元修复过程中神经胶质细胞重塑细胞外微环境结构的全新机制。