Senescent Schwann cells induced by aging and chronic denervation impair axonal regeneration following peripheral nerve injury
Abstract 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 a...
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| Format: | Article |
| Language: | English |
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Springer Nature
2023-10-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202317907 |
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| author | Andrés Fuentes‐Flores Cristian Geronimo‐Olvera Karina Girardi David Necuñir‐Ibarra Sandip Kumar Patel Joanna Bons Megan C Wright Daniel Geschwind Ahmet Hoke Jose A Gomez‐Sanchez Birgit Schilling Daniela L Rebolledo Judith Campisi Felipe A Court |
| author_facet | Andrés Fuentes‐Flores Cristian Geronimo‐Olvera Karina Girardi David Necuñir‐Ibarra Sandip Kumar Patel Joanna Bons Megan C Wright Daniel Geschwind Ahmet Hoke Jose A Gomez‐Sanchez Birgit Schilling Daniela L Rebolledo Judith Campisi Felipe A Court |
| author_sort | Andrés Fuentes‐Flores |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-81de24a7030f424a99feff5a63cbe0ba |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2023-10-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-81de24a7030f424a99feff5a63cbe0ba2025-08-20T03:46:19ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-10-01151211810.15252/emmm.202317907Senescent Schwann cells induced by aging and chronic denervation impair axonal regeneration following peripheral nerve injuryAndrés Fuentes‐Flores0Cristian Geronimo‐Olvera1Karina Girardi2David Necuñir‐Ibarra3Sandip Kumar Patel4Joanna Bons5Megan C Wright6Daniel Geschwind7Ahmet Hoke8Jose A Gomez‐Sanchez9Birgit Schilling10Daniela L Rebolledo11Judith Campisi12Felipe A Court13Center for Integrative Biology, Faculty of Sciences, Universidad MayorCenter for Integrative Biology, Faculty of Sciences, Universidad MayorCenter for Integrative Biology, Faculty of Sciences, Universidad MayorCenter for Integrative Biology, Faculty of Sciences, Universidad MayorBuck Institute for Research on AgingBuck Institute for Research on AgingDepartments of Neurology and Neuroscience, Johns Hopkins School of MedicineDepartments of Neurology, Psychiatry, and Human Genetics, David Geffen School of Medicine, University of California Los AngelesDepartments of Neurology and Neuroscience, Johns Hopkins School of MedicineInstituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL)Buck Institute for Research on AgingCenter for Integrative Biology, Faculty of Sciences, Universidad MayorBuck Institute for Research on AgingCenter for Integrative Biology, Faculty of Sciences, Universidad MayorAbstract 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.https://doi.org/10.15252/emmm.202317907agingchronic denervationnerve regenerationSchwann cellsenescence |
| spellingShingle | Andrés Fuentes‐Flores Cristian Geronimo‐Olvera Karina Girardi David Necuñir‐Ibarra Sandip Kumar Patel Joanna Bons Megan C Wright Daniel Geschwind Ahmet Hoke Jose A Gomez‐Sanchez Birgit Schilling Daniela L Rebolledo Judith Campisi Felipe A Court Senescent Schwann cells induced by aging and chronic denervation impair axonal regeneration following peripheral nerve injury EMBO Molecular Medicine aging chronic denervation nerve regeneration Schwann cell senescence |
| title | Senescent Schwann cells induced by aging and chronic denervation impair axonal regeneration following peripheral nerve injury |
| title_full | Senescent Schwann cells induced by aging and chronic denervation impair axonal regeneration following peripheral nerve injury |
| title_fullStr | Senescent Schwann cells induced by aging and chronic denervation impair axonal regeneration following peripheral nerve injury |
| title_full_unstemmed | Senescent Schwann cells induced by aging and chronic denervation impair axonal regeneration following peripheral nerve injury |
| title_short | Senescent Schwann cells induced by aging and chronic denervation impair axonal regeneration following peripheral nerve injury |
| title_sort | senescent schwann cells induced by aging and chronic denervation impair axonal regeneration following peripheral nerve injury |
| topic | aging chronic denervation nerve regeneration Schwann cell senescence |
| url | https://doi.org/10.15252/emmm.202317907 |
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