Cimpean Anda, Roll Lars, Reinhard Jacqueline, Kwok Jessica C F, Faissner Andreas, de Winter Fred, Fawcett James W, Jendelová Pavla
Institute of Experimental Medicine, Czech Academy of Science, Prague, Czechia.
Second Faculty of Medicine, Charles University, Prague, Czechia.
Front Cell Neurosci. 2025 Apr 1;19:1568004. doi: 10.3389/fncel.2025.1568004. eCollection 2025.
Spinal cord injury involves complex pathobiological mechanisms, necessitating a multidimensional approach for its cure. Previous studies have shown that α9-integrin expression and activation in mature dorsal root ganglion neurons enable the regeneration of injured axons within the spinal cord. However, tissue cavitation and fibrosis impede the regenerating axons from following their usual pathways, forcing them to seek alternative routes rich in tenascin-C, the primary ligand of the integrin. Fibrin gel, an FDA-approved and biocompatible material, can offer three-dimensional support for axonal extension through the cavitated area, thus preventing the formation of aberrant paths and connections that occur in the absence of a suitable scaffold.
The aim of this study was to investigate how combining α9-integrin expression by adeno-associated virus with the use of a fibrin gel as an extracellular microenvironment affects the growth of mature DRG neurites . Additionally, we sought to functionalize fibrin with integrin ligand peptides, specifically AEIDGIEL, the active domain of tenascin-C, to ensure α9-integrin activation.
Our results indicate that fibrin gels are a suitable biomaterial for promoting neurite growth and that AEIDGIEL peptide effectively activates the integrin. Furthermore, we corroborate an autocrine signaling loop of α9-integrin and TN-C produced by neurons.
the proposed combination therapy of α9-integrin and fibrin gel biomaterials incorporating AEIDGIEL peptide shows promise for addressing the complex challenges of spinal cord injury and promoting effective neural regeneration, laying the foundation for further research.
脊髓损伤涉及复杂的病理生物学机制，需要采用多维度方法进行治疗。先前的研究表明，成熟背根神经节神经元中α9整合素的表达和激活能够使脊髓内受损轴突再生。然而，组织空洞化和纤维化阻碍再生轴突沿其通常路径生长，迫使它们寻找富含腱生蛋白-C（整合素的主要配体）的替代路径。纤维蛋白凝胶是一种经美国食品药品监督管理局批准的生物相容性材料，可为轴突通过空洞区域延伸提供三维支持，从而防止在缺乏合适支架的情况下形成异常路径和连接。
本研究的目的是探讨腺相关病毒介导的α9整合素表达与使用纤维蛋白凝胶作为细胞外微环境相结合如何影响成熟背根神经节神经突的生长。此外，我们试图用整合素配体肽（特别是腱生蛋白-C的活性结构域AEIDGIEL）对纤维蛋白进行功能化，以确保α9整合素的激活。
我们的结果表明，纤维蛋白凝胶是促进神经突生长的合适生物材料，且AEIDGIEL肽能有效激活整合素。此外，我们证实了神经元产生的α9整合素和腱生蛋白-C的自分泌信号回路。
所提出的α9整合素与包含AEIDGIEL肽的纤维蛋白凝胶生物材料的联合疗法有望应对脊髓损伤的复杂挑战并促进有效的神经再生，为进一步研究奠定基础。
