Following peripheral nerve injury, successful axonal growth and functional recovery require Schwann cell (SC) reprogramming into a reparative phenotype, a process dependent upon c-Jun transcription factor activation. Unfortunately, axonal regeneration is greatly impaired in aged organisms and following chronic denervation, which can lead to poor clinical outcomes. While diminished c-Jun expression in SCs has been associated with regenerative failure, it is unclear whether the inability to maintain a repair state is associated with the transition into an axonal growth inhibition phenotype. We here find that reparative SCs transition into a senescent phenotype, characterized by diminished c-Jun expression and secretion of inhibitory factors for axonal regeneration in aging and chronic denervation. In both conditions, the elimination of senescent SCs by systemic senolytic drug treatment or genetic targeting improved nerve regeneration and functional recovery, increased c-Jun expression and decreased nerve inflammation. This work provides the first characterization of senescent SCs and their influence on axonal regeneration in aging and chronic denervation, opening new avenues for enhancing regeneration and functional recovery after peripheral nerve injuries.

中文翻译：

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衰老和慢性去神经引起的衰老雪旺细胞会损害周围神经损伤后的轴突再生


周围神经损伤后，成功的轴突生长和功能恢复需要雪旺细胞 (SC) 重新编程为修复表型，这一过程依赖于 c-Jun 转录因子的激活。不幸的是，衰老生物体和慢性去神经支配后的轴突再生受到严重损害，这可能导致临床结果不佳。虽然 SC 中 c-Jun 表达的减少与再生失败有关，但尚不清楚无法维持修复状态是否与轴突生长抑制表型的转变有关。我们发现修复性 SC 转变为衰老表型，其特征是 c-Jun 表达减少，以及衰老和慢性去神经支配中轴突再生抑制因子的分泌减少。在这两种情况下，通过全身性抗衰老药物治疗或基因靶向消除衰老的 SC，可改善神经再生和功能恢复，增加 c-Jun 表达并减少神经炎症。这项工作首次描述了衰老 SC 的特征及其对衰老和慢性去神经支配中轴突再生的影响，为增强周围神经损伤后的再生和功能恢复开辟了新途径。