American Society for Peripheral Nerve

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Side-to-side nerve bridges support donor axon regeneration into chronically denervated nerves and are associated with characteristic changes in Schwann cell phenotype and re-myelination
J. Mike Hendry, MD1; M. Cecilia Alvarez-Veronesi1; Alison K. Snyder, MD2; Tessa Gordon, PhD1; Gregory H. Borschel, MD1
1Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, Toronto, ON, Canada; 2Plastic Surgery, Washington University School of Medicine, Saint Louis, MO

Introduction: Chronic denervation resulting from long nerve regeneration times and distances is a major contributor to suboptimal regenerative outcomes following nerve injuries. Recent studies showed that nerve grafts between an intact donor nerve and a denervated distal recipient nerve stump (termed side-to-side nerve bridges) enhanced the regenerative success after delayed nerve repair. In this study, we addressed the cellular aspects of axon growth across these bridges to evaluate the basis for this ‘protection’ of the chronically denervated Schwann cells by the donor nerves.

Materials & Methods: In Sprague Dawley rats whose neurons express green fluorescent (GFP), three side-to-side nerve bridges were placed bilaterally over a 10 mm distance between opposing epineurial windows of an intact tibial (TIB) nerve and a distal denervated common peroneal (CP) nerve stump. Numbers of axons that grew across the bridges were counted in cross-section after 4 weeks. Immunofluorescent imaging of axons and Schwann cells were imaged and semi-quantitated over a 4 month period.

Results: Side-to-side nerve bridges supported the growth of donor axons across and into the denervated CP nerve stumps. Denervated Schwann cells dedifferentiated to a proliferative, non-myelinating phenotype within the bridges as well as the recipient denervated CP nerve stump after injury. Schwann cells demonstrated strong p75 immunoreactivity and redifferentiated to a myelinating phenotype with expression of myelin basic protein after ingrowth of donor axons. Side-to-side nerve bridges promoted a relative increase in wet muscle mass of tibialis anterior and extensor digitorum longus muscles in the anterior hindlimb compartment as compared the mass of the muscles whose common peroneal nerve was not ‘protected’ by cross-bridges.

Conclusions: This study documents the pattern of donor axon regeneration and myelination into the denervated recipient nerve stump that supports a mechanism where ingrowing axons sustain a pro-regenerative state in a denervated nerve pathway that would otherwise have deteriorated in the face of chronic denervation.

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