Abstract

Nerve regeneration is a key biological process in those recovering from neural trauma. From animal models it is known that the regenerative capacity of the peripheral nervous system (PNS) relies heavily on the remarkable ability of Schwann cells to undergo a phenotypic shift from a myelinating phenotype to one that is supportive of neural regeneration. In rodents, a great deal is known about the molecules that control this process, such as the transcription factors c-Jun and early growth response protein 2 (EGR2/KROX20), or mark the cells and cellular changes involved, including SOX10 and P75 neurotrophin receptor (p75NTR). However, ethical and practical challenges associated with studying human nerve injury have meant that little is known about human nerve regeneration.The present study addresses this issue, analysing 34 denervated and five healthy nerve samples from 27 patients retrieved during reconstructive nerve procedures. Using immunohistochemistry and Real-Time quantitative Polymerase Chain Reaction (RT-qPCR), the expression of SOX10, c-Jun, p75NTR and EGR2 was assessed in denervated samples and compared to healthy nerve. Nonparametric smoothing linear regression was implemented to better visualise trends in the expression of these markers across denervated samples.It was found, first, that two major genes associated with repair Schwann cells in rodents, c-Jun and p75NTR, are also up-regulated in acutely injured human nerves, while the myelin associated transcription factor EGR2 is down-regulated, observations that encourage the view that rodent models are relevant for learning about human nerve injury. Second, as in rodents, the expression of c-Jun and p75NTR declines during long-term denervation. In rodents, diminishing c-Jun and p75NTR levels mark the general deterioration of repair cells during chronic denervation, a process thought to be a major obstacle to effective nerve repair. The down-regulation of c-Jun and p75NTR reported here provides the first molecular evidence that also in humans, repair cells deteriorate during chronic denervation.

Highlights

  • Peripheral Nerve Injury (PNI) results in partial or complete loss of sensory and/or motor function and involvement of sympathetic and pain systems in the body segment involved

  • Thirty four denervated and five healthy nerve samples were included in the study, from 26 males and one female

  • In summary, this study provides new insights into some of the key cellular and molecular features that underpin the regenerative capacity of the human Peripheral Nervous System (PNS), providing additional explanations for clinical observations and reports

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Summary

Introduction

Peripheral Nerve Injury (PNI) results in partial or complete loss of sensory and/or motor function and involvement of sympathetic and pain systems in the body segment involved. Rodent studies have established that this can largely be attributed to adverse changes in Schwann cells and their associated basal laminae, including reduced expression of repair-supportive molecules and decreasing Schwann cell numbers [12,13,14]. This process is thought to be a major obstacle to effective nerve repair, this progressive loss of regeneration support has not been investigated in detail in humans

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