Li C, Rassekh N, O'Daly A, Kebaisch F, Wolinsky R, Vyas A, Skolasky R, Hoke A, Brushart T
Department of Orthopaedic Surgery, Johns Hopkins University, 601 N Caroline St, Baltimore, MD 21287, United States of America.
Department of Neurology, Johns Hopkins University, 855 N Wolfe St, Baltimore, MD 21287, United States of America; The Solomon H Snyder Department of Neuroscience, Johns Hopkins University, 725 N Wolfe St, Baltimore, MD 21205, United States of America.
Exp Neurol. 2025 Mar;385:115066. doi: 10.1016/j.expneurol.2024.115066. Epub 2024 Nov 21.
To restore function after nerve injury, axons must regenerate from the injury site to the periphery, then reinnervate appropriate end organs when they arrive. Only 10 % of adults who suffer nerve injury will regain normal function, often because axons regenerate to functionally inappropriate targets (Brushart, 2011). The peripheral destination of these axons is largely determined by the pathways they enter at the site of nerve repair. To improve clinical outcomes, it is thus critical to improve the accuracy of axon pathfinding. In rodents, motor axons regenerating in mixed nerve preferentially reinnervate pathways leading to muscle, a process termed preferential motor reinnervation (PMR). Previous experiments have shown that PMR can be enhanced by predegenerating nerve grafts to enhance growth factor production and remove inhibitory factors (Abdullah et al., 2013). The current experiments explore the relative contributions of motor pathways, sensory pathways, and the repair environment to this enhancement. Sensory and/or motor pathways within rat femoral nerve grafts were predegenerated for 3 weeks to optimize growth factor production (Brushart et al., 2013) or for 12 weeks to deplete it. Optimizing the environment within previously motor Schwann cell tubes promoted PMR, regardless of whether adjacent sensory pathways were optimized or chronically denervated. However, this positive effect was abolished when sensory pathways were undergoing acute Wallerian degeneration immediately after nerve repair. The repair environment thus precluded motor axon pathfinding in spite of an optimized distal motor pathway. When sensory pathways were optimized and motor pathways were chronically denervated, not only was PMR abolished, but motoneurons failed to respond to the greater volume of growth factors in the sensory nerve. Small sensory neurons, however, selectively reinnervated cutaneous nerve under these conditions. These experiments thus strengthen the concept that, in adult rats, sensory and motor pathways have unique identities capable of influencing both sensory and motor axon regeneration. Furthermore, they demonstrate that, in the rat, delaying nerve repair for 3 weeks to enhance growth factor production and clear the products of acute Wallerian degeneration can enhance regeneration specificity without the need for exogenous treatments.
为了在神经损伤后恢复功能，轴突必须从损伤部位向周围再生，然后在到达时重新支配合适的终末器官。只有10%的成年神经损伤患者能够恢复正常功能，这通常是因为轴突再生到了功能不适当的靶点（Brushart，2011）。这些轴突的外周目的地很大程度上取决于它们在神经修复部位进入的通路。因此，为了改善临床结果，提高轴突寻路的准确性至关重要。在啮齿动物中，混合神经中再生的运动轴突优先重新支配通向肌肉的通路，这一过程称为优先运动再支配（PMR）。先前的实验表明，通过预先使神经移植物退变以增强生长因子的产生并去除抑制因子，可以增强PMR（Abdullah等人，2013）。当前的实验探讨了运动通路、感觉通路和修复环境对这种增强作用的相对贡献。大鼠股神经移植物中的感觉和/或运动通路预先退变3周以优化生长因子的产生（Brushart等人，2013）或退变12周以耗尽生长因子。优化先前运动雪旺氏细胞管内的环境可促进PMR，无论相邻的感觉通路是优化的还是长期失神经支配的。然而，当感觉通路在神经修复后立即发生急性沃勒氏变性时，这种积极作用就被消除了。因此，尽管远端运动通路已优化，但修复环境仍妨碍了运动轴突的寻路。当感觉通路优化而运动通路长期失神经支配时，不仅PMR被消除，而且运动神经元对感觉神经中更多的生长因子也没有反应。然而，在这些条件下，小感觉神经元选择性地重新支配皮神经。因此，这些实验强化了这样一个概念，即在成年大鼠中，感觉和运动通路具有独特的特性，能够影响感觉和运动轴突的再生。此外，它们还表明，在大鼠中，将神经修复延迟3周以增强生长因子的产生并清除急性沃勒氏变性的产物，可以增强再生特异性，而无需进行外源治疗。
