Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK.
British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, James Black Centre, King's College London, London, UK.
Nat Commun. 2020 Dec 21;11(1):6425. doi: 10.1038/s41467-020-20179-z.
Overcoming the restricted axonal regenerative ability that limits functional repair following a central nervous system injury remains a challenge. Here we report a regenerative paradigm that we call enriched conditioning, which combines environmental enrichment (EE) followed by a conditioning sciatic nerve axotomy that precedes a spinal cord injury (SCI). Enriched conditioning significantly increases the regenerative ability of dorsal root ganglia (DRG) sensory neurons compared to EE or a conditioning injury alone, propelling axon growth well beyond the spinal injury site. Mechanistically, we established that enriched conditioning relies on the unique neuronal intrinsic signaling axis PKC-STAT3-NADPH oxidase 2 (NOX2), enhancing redox signaling as shown by redox proteomics in DRG. Finally, NOX2 conditional deletion or overexpression respectively blocked or phenocopied enriched conditioning-dependent axon regeneration after SCI leading to improved functional recovery. These studies provide a paradigm that drives the regenerative ability of sensory neurons offering a potential redox-dependent regenerative model for mechanistic and therapeutic discoveries.
克服中枢神经系统损伤后限制功能修复的有限轴突再生能力仍然是一个挑战。在这里，我们报告了一种我们称之为丰富条件作用的再生范例，它将环境富集（EE）与坐骨神经预先切断的条件作用相结合，然后再进行脊髓损伤（SCI）。与 EE 或单独的条件作用损伤相比，丰富的条件作用显著增加了背根神经节（DRG）感觉神经元的再生能力，使轴突生长远远超过脊髓损伤部位。从机制上讲，我们确定丰富的条件作用依赖于独特的神经元内在信号轴 PKC-STAT3-NADPH 氧化酶 2（NOX2），如 DRG 中的氧化还原蛋白质组学所示，增强氧化还原信号。最后，NOX2 条件性缺失或过表达分别阻断或模拟了 SCI 后丰富条件作用依赖性轴突再生，导致功能恢复改善。这些研究提供了一种驱动感觉神经元再生能力的范例，为机制和治疗发现提供了一种潜在的氧化还原依赖性再生模型。
