Abstract：
Epidural fibrosis (EF), associated with various biological factors, is still a major troublesome clinical problem after laminectomy. In the present study, we initially demonstrate that sensory nerves can attenuate fibrogenic progression in EF animal models via the secretion of calcitonin gene-related peptide (CGRP), suggesting a new potential therapeutic target. Further studies showed that CGRP could inhibit the reprograming activation of fibroblasts through PI3K/AKT signal pathway. We subsequently identified metformin (MET), the most widely prescribed medication for obesity-associated type 2 diabetes, as a potent stimulator of sensory neurons to release more CGRP via activating CREB signal way. We copolymerized MET with innovative polycaprolactone (PCL) nanofibers to develop a metformin-grafted PCL nanoscaffold (METG-PCLN), which could ensure stable long-term drug release and serve as favorable physical barriers. In vivo results demonstrated that local implantation of METG-PCLN could penetrate into dorsal root ganglion cells (DRGs) to promote the CGRP synthesis, thus continuously inhibit the fibroblast activation and EF progress for 8 weeks after laminectomy, significantly better than conventional drug loading method. In conclusion, this study reveals the unprecedented potential of sensory neurons to counteract EF through CGRP signaling and introduces a novel strategy employing METG-PCLN to obstruct EF by fine-tuning sensory nerve-regulated fibrogenesis.
摘要：
硬膜外纤维化（EF），与各种生物因素有关，椎板切除术后仍然是一个主要的麻烦的临床问题。在本研究中,我们初步证明，在EF动物模型中，感觉神经可以通过降钙素基因相关肽（CGRP）的分泌减弱纤维化进展，提出了新的潜在治疗靶点。进一步研究表明，CGRP可以通过PI3K/AKT信号通路抑制成纤维细胞的重编程活化。我们随后确定了二甲双胍（MET），最广泛的治疗肥胖相关2型糖尿病的药物，作为感觉神经元的有效刺激器，通过激活CREB信号方式释放更多的CGRP。我们将MET与创新的聚己内酯（PCL）纳米纤维共聚，以开发二甲双胍接枝的PCL纳米支架（METG-PCLN），这可以确保稳定的长期药物释放，并作为有利的物理屏障。体内实验结果表明,METG-PCLN的局部植入可以穿透背根神经节细胞(DRGs)促进CGRP的合成,因此连续抑制成纤维细胞活化和EF进展8周后，显著优于常规载药法。总之,这项研究揭示了感觉神经元通过CGRP信号传导抵消EF的前所未有的潜力，并引入了一种采用METG-PCLN通过微调感觉神经调节的纤维发生来阻断EF的新策略。
