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Delayed Nerve Repair is Affected by Irreversible Changes Occurring in Long-term Denervated Schwann Cells
Stefania Raimondo, PhD1; Giulia Ronchi, PhD1; Giovanna Gambarotta, PhD1; Benedetta Elena Fornasari, BSC1; Bruno Battiston, MD2; Pierluigi Tos, MD, PhD3; Stefano Geuna, MD1
1University of Turin, Orbassano, Torino, Italy, 2Microsurgery Unit, CTO Hospital, Torino, Italy, 3UO di Microshirurgia Ricostruttiva, UO di microchirurgia ricostruttiva, Ospedale Gaetano Pini, Milano, Italy
Introduction: The complete recovery after peripheral nerve injury does not always occur and can be influenced by many factors including patient age, lesion site, injury severity, size of the gap between damaged nerve stumps and time interval that elapses before performing surgical repair. The poor outcome occurring after a long delay can be due to loss of the neuron ability to regenerate, loss of the Schwann cell ability to support regeneration and, of course, progressive muscle atrophy. The aim of this study was to investigate the nerve regeneration after delayed repair and to study the degenerative processes of the denervated distal nerve stump.
Materials and Methods: A rat surgical model of delayed nerve repair consisting of a cross suture between the chronically degenerated median nerve distal stump (3 and 6 months) and the freshly axotomized ulnar proximal stump was used. Functional, morphological, morphometrical and biomolecular analyses were carried out on regenerated distal nerve stumps 6 months after nerve repair.
Results: Morphological and biomolecular analyses carried out on degenerated nerves showe atrophic Schwann cells, several collagen fibers and fibroblasts and a significant reduction of soluble Neureguli1 (NRG1, an important factor for the survival and activity of Schwann cells) already after 3 months of degeneration. Functional recovery analysis performed after nerve repair shows that only the group repaired immediately and not the two delayed-repaired groups, recovered partially. Moreover, quantitative analysis shows that the delayed groups has fewer and smaller myelinated fibers compared to the immediate repair group. Finally, biomolecular analysis performed on the 6-months delayed group shows that soluble NRG1 maintains a low expression also after 6 months of regeneration.
Conclusions: These results demonstrate that, despite a delay of 3 or 6 months, the fibers are still able to regenerate, even if they are fewer and smaller than the immediate repaired group. Moreover, the analysis of the NRG1/ErbB system shows a significant decrease of soluble NRG1 in both degenerating and delayed-repaired nerves. Our results suggest that NRG1 plays an important role in Schwann cell activity after denervation, therefore its manipulation could be a good strategy to improve the outcome after delayed nerve repair.
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