Coordinated changes in the expression of Wnt pathway genes following human and rat peripheral nerve injury.

Arie C Van Vliet,Fred De Winter,Martijn J A Malessy,Matthew R J Mason,Jinhui Lee,Jasprina N Noordermeer,Joost Verhaagen,Martijn R Tannemaat,Marlijn Van Der Poel,Lee G Fradkin

doi:10.1371/journal.pone.0249748

Abstract

A human neuroma-in continuity (NIC), formed following a peripheral nerve lesion, impedes functional recovery. The molecular mechanisms that underlie the formation of a NIC are poorly understood. Here we show that the expression of multiple genes of the Wnt family, including Wnt5a, is changed in NIC tissue from patients that underwent reconstructive surgery. The role of Wnt ligands in NIC pathology and nerve regeneration is of interest because Wnt ligands are implicated in tissue regeneration, fibrosis, axon repulsion and guidance. The observations in NIC prompted us to investigate the expression of Wnt ligands in the injured rat sciatic nerve and in the dorsal root ganglia (DRG). In the injured nerve, four gene clusters were identified with temporal expression profiles corresponding to particular phases of the regeneration process. In the DRG up- and down regulation of certain Wnt receptors suggests that nerve injury has an impact on the responsiveness of injured sensory neurons to Wnt ligands in the nerve. Immunohistochemistry showed that Schwann cells in the NIC and in the injured nerve are the source of Wnt5a, whereas the Wnt5a receptor Ryk is expressed by axons traversing the NIC. Taken together, these observations suggest a central role for Wnt signalling in peripheral nerve regeneration.

Highlights

Peripheral nerve injuries can cause life-long functional disability in patients
To gain insight in the gene expression changes that occur in human neuroma-in-continuity (NIC) a micro-array analysis was performed on NIC tissue of eight patients after neonatal brachial plexus injury (NBPI)
Sections of the proximal nerve adjacent of the NIC were examined during the reconstructive surgery and the proximal stump was considered a healthy nerve as 80% or more of transversal section surface had a normal organized nerve structure and myelin

Summary

Introduction

The regenerative response of an injured peripheral nerve is dependent on a variety of parameters, including the age of the patient, the distance of the lesion to the end organs, and the severity of the injury [1]. Changes in Wnt pathway genes following human and rat peripheral nerve injury human nerve culminates in the formation of a neuroma-in-continuity (NIC). The biological processes that underlie the formation of a NIC following injury and how the NIC inhibits functional recovery remain poorly understood. In an effort to delineate the changes in gene expression that occur in an injured human peripheral nerve, Tannemaat et al performed a microarray analysis on NIC tissue derived from eight patients with severe brachial plexus injury [2]. In an effort to delineate the changes in gene expression that occur in an injured human peripheral nerve, Tannemaat et al performed a microarray analysis on NIC tissue derived from eight patients with severe brachial plexus injury [2]. 722 genes were differentially expressed in the NIC compared to the proximal nerve stump

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