Division of Neuroanatomy, Department of Anatomy and Histology, Innsbruck Medical University, Innsbruck, Austria.
Int Rev Neurobiol. 2013;108:137-71. doi: 10.1016/B978-0-12-410499-0.00006-X.
Injury to a peripheral nerve induces a complex cellular and molecular response required for successful axon regeneration. Proliferating Schwann cells organize into chains of cells bridging the lesion site, which is invaded by macrophages. Approximately half of the injured neuron population sends out axons that enter the glial guidance channels in response to secreted neurotrophic factors and neuropoietic cytokines. These lesion-associated polypeptides create an environment that is highly supportive for axon regrowth, particularly after acute injury, and ensure that the vast majority of regenerating axons are directed toward the distal nerve stump. Unfortunately, most neurotrophic factors and neuropoietic cytokines are also strong stimulators of axonal sprouting. Although some of the axonal branches will withdraw at later stages, the sprouting effect contributes to the misdirection of reinnervation that results in the lack of functional recovery observed in many patients with peripheral nerve injuries. Here, we critically review the role of neuronal growth factors and cytokines during axon regeneration in the peripheral nervous system. Their differential effects on axon elongation and sprouting were elucidated in various studies on intraneuronal signaling mechanisms following nerve lesion. The present data define a goal for future therapeutic strategies, namely, to selectively stimulate a Ras/Raf/ERK-mediated axon elongation program over an intrinsic PI3K-dependent axonal sprouting program in lesioned motor and sensory neurons. Instead of modulating growth factor or cytokine levels at the lesion site, targeting specific intraneuronal molecules, such as the negative feedback inhibitors of ERK signaling, has been shown to promote long-distance regeneration while avoiding sprouting of regenerating axons until they have reached their target areas.
外周神经损伤会引起复杂的细胞和分子反应，这是轴突再生成功所必需的。增殖的施万细胞组织成细胞链，桥接损伤部位，该部位被巨噬细胞侵入。大约一半的损伤神经元种群会发出轴突，这些轴突会在分泌的神经营养因子和神经生成细胞因子的作用下进入神经胶质导向通道。这些与损伤相关的多肽会创造一个非常有利于轴突再生的环境，特别是在急性损伤后，并确保绝大多数再生轴突都被引导到远端神经残端。不幸的是，大多数神经营养因子和神经生成细胞因子也是轴突发芽的强烈刺激物。虽然一些轴突分支会在后期撤回，但发芽效应有助于错误引导再神经支配，导致许多外周神经损伤患者观察到缺乏功能恢复。在这里，我们批判性地回顾了神经元生长因子和细胞因子在外周神经系统轴突再生中的作用。它们对轴突伸长和发芽的不同影响在神经损伤后神经元内信号转导机制的各种研究中得到了阐明。目前的数据为未来的治疗策略定义了一个目标，即选择性地刺激 Ras/Raf/ERK 介导的轴突伸长程序，而不是 PI3K 依赖性内在轴突发芽程序，在受损的运动和感觉神经元中。靶向特定的神经元内分子，如 ERK 信号的负反馈抑制剂，而不是调节损伤部位的生长因子或细胞因子水平，已被证明可以促进远距离再生，同时避免再生轴突发芽，直到它们到达目标区域。
