• J Michael Hendry, M Cecilia Alvarez-Veronesi, Alison Snyder-Warwick, Tessa Gordon, and Gregory H Borschel.
• *Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, Toronto, ON, Canada; ‡Department of Surgery, §Institute of Medical Science, and ¶Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada; ‖SickKids Research Institute Program in Neuroscience, Toronto, ON, Canada.
• Neurosurgery. 2015 Nov 1; 77 (5): 803-13.

BackgroundChronic denervation resulting from long nerve regeneration times and distances contributes greatly to suboptimal outcomes following nerve injuries. Recent studies showed that multiple nerve grafts inserted between an intact donor nerve and a denervated distal recipient nerve stump (termed "side-to-side nerve bridges") enhanced regeneration after delayed nerve repair.ObjectiveTo examine the cellular aspects of axon growth across these bridges to explore the "protective" mechanism of donor axons on chronically denervated Schwann cells.MethodsIn Sprague Dawley rats, 3 side-to-side nerve bridges were placed over a 10-mm distance between an intact donor tibial (TIB) nerve and a recipient denervated common peroneal (CP) distal nerve stump. Green fluorescent protein-expressing TIB axons grew across the bridges and were counted in cross section after 4 weeks. Immunofluorescent axons and Schwann cells were imaged over a 4-month period.ResultsDenervated Schwann cells dedifferentiated to a proliferative, nonmyelinating phenotype within the bridges and the recipient denervated CP nerve stump. As donor TIB axons grew across the 3 side-to-side nerve bridges and into the denervated CP nerve, the Schwann cells redifferentiated to the myelinating phenotype. Bridge placement led to an increased mass of hind limb anterior compartment muscles after 4 months of denervation compared with muscles whose CP nerve was not "protected" by bridges.ConclusionThis study describes patterns of donor axon regeneration and myelination in the denervated recipient nerve stump and supports a mechanism where these donor axons sustain a proregenerative state to prevent deterioration in the face of chronic denervation.

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