Peripheral nerve derived fibroblasts promote neurite outgrowth in adult dorsal root ganglion neurons more effectively than skin-derived fibroblasts

Although fibroblasts (Fb) partially consist of peripheral nerves and are involved in the regenerative process associated with a peripheral nerve injury (PNI), detailed information regarding their characteristics is largely lacking. The objective of the current study was to investigate the capacity of Fb derived from peripheral nerves to stimulate the outgrowth of neurites from adult dorsal root ganglion (DRG) neurons and to clarify their molecular characteristics. Fb were primally prepared from the epineurium (Epn) and parenchyma (Par) of rat sciatic nerves and skin (Skn). The Fb derived from Epn (Fb-Epn) showed the greatest neurite outgrowth effect, followed by the Fb derived from parenchyma (Fb-Par), indicating that Fb derived from nerves promote neurite outgrowth more effectively than Skn-derived Fb (Fb-Skn). Although both secreted and cell-surface factors contributed evenly to the neurite promoting effect of nerve derived Fb, in crush and transection injury models, Fb were not closely associated with regenerating axons, indicating that only factors that are secreted from Fb are available to regenerating axons. A transcriptome analysis revealed that the molecular profiles of these Fb were distinctly different and that the gene expression profiles of secreted factors that promote axonal growth are unique to each Fb. These findings indicate that Fb are molecularly and functionally different depending on their localization in nerve tissue and that Fb-Epn might be involved more than was previously thought in axon regeneration after PNI.尽管成纤维细胞（fibroblasts, Fb）是外周神经的组成成分之一，且参与外周神经损伤（peripheral nerve injury, PNI）相关的再生进程，但目前针对其特征的详细研究资料仍较为匮乏。本研究旨在探究源自外周神经的成纤维细胞刺激成年背根神经节（dorsal root ganglion, DRG）神经元神经突生长的能力，并阐明其分子特征。研究人员首先从大鼠坐骨神经的神经外膜（epineurium, Epn）、神经实质（parenchyma, Par）以及皮肤（skin, Skn）中分离得到原代成纤维细胞。实验结果显示，源自神经外膜的成纤维细胞（Fb-Epn）的神经突促生长效果最为显著，其次为源自神经实质的成纤维细胞（Fb-Par），这表明神经来源的成纤维细胞相较于皮肤来源的成纤维细胞（Fb-Skn），能更有效地促进神经突生长。尽管分泌型因子与细胞表面因子对神经来源成纤维细胞的神经突促生长作用均有均等贡献，但在挤压损伤与横断损伤模型中，成纤维细胞并未与再生轴突紧密结合，这提示唯有成纤维细胞分泌的因子可作用于再生轴突。转录组分析结果显示，不同来源的成纤维细胞分子特征存在显著差异，且各类促轴突生长的分泌型因子的基因表达谱各具特异性。上述研究结果表明，成纤维细胞的分子特征与功能会因其在神经组织中的定位不同而存在差异，且神经外膜来源的成纤维细胞（Fb-Epn）可能在外周神经损伤后的轴突再生过程中，发挥了比此前认知更为重要的作用。