Senescent Schwann cells induced by aging and chronic denervation impair axonal regeneration following peripheral nerve injury

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. imageFollowing nerve damage of aged nerves or delayed repair, Schwann cells (SCs) are less able to transition into the reparative phenotype necessary for axonal regrowth. Here, SCs from chronically denervated or aged conditions are characterized to better understand their influence on regeneration.Schwann cells from aged and chronic denervation mice transition into a senescent phenotype.Chronically denervated and aged nerves present a proinflammatory profile and upregulation of Senescent-associated Secretory Phenotype-related genes.Secreted factors from senescent SCs inhibit axonal growth of sensory neurons.Senescent cell elimination restores a reparative SC phenotype and decreases injury-induced nerve inflammation in aged and chronically denervated animals.Elimination of senescent cells improves nerve regeneration in aging and chronic denervation. Following nerve damage of aged nerves or delayed repair, Schwann cells (SCs) are less able to transition into the reparative phenotype necessary for axonal regrowth. Here, SCs from chronically denervated or aged conditions are characterized to better understand their influence on regeneration.image