Advancing Our Understanding of the Chronically Denervated Schwann Cell: A Potential Therapeutic Target?

Abstract

Outcomes for patients following major peripheral nerve injury are extremely poor. Despite advanced microsurgical techniques, the recovery of function is limited by an inherently slow rate of axonal regeneration. In particular, a time-dependent deterioration in the ability of the distal stump to support axonal growth is a major determinant to the failure of reinnervation. Schwann cells (SC) are crucial in the orchestration of nerve regeneration; their plasticity permits the adoption of a repair phenotype following nerve injury. The repair SC modulates the initial immune response, directs myelin clearance, provides neurotrophic support and remodels the distal nerve. These functions are critical for regeneration; yet the repair phenotype is unstable in the setting of chronic denervation. This phenotypic instability accounts for the deteriorating regenerative support offered by the distal nerve stump. Over the past 10 years, our understanding of the cellular machinery behind this repair phenotype, in particular the role of c-Jun, has increased exponentially, creating opportunities for therapeutic intervention. This review will cover the activation of the repair phenotype in SC, the effects of chronic denervation on SC and current strategies to 'hack' these cellular pathways toward supporting more prolonged periods of neural regeneration.

Keywords: Schwann cells; c-Jun; chronic Schwann cell denervation; nerve injury; peripheral nerve injury; peripheral nerve regeneration.

Figure 1

(A) Following axotomy, SC undergo a phenotypic switch to a repair phenotype. This switch involves the suppression of genes associated with myelination, e.g., MPZ/MBP/MAG, and the upregulation of c-Jun/Shh/GDNF/STAT3, which initiate the repair phenotype. In this state, SC initiate an immune response through the release of cytokines (e.g., TNF-α) and monocyte chemotractants (e.g., MCP-1). They activate macrophages and alongside macrophages phagocytose myelin. (B) The activation of c-Jun in SC initiates considerable morphological changes with extensive elongation forming the bands of Büngner, remodelling the distal stump, and bridging nerve gaps. Concurrently, they secrete neurotrophins to support and guide axonal regeneration. With chronic denervation and over time, this repair phenotype is ultimately lost.

Figure 2

The identification of c-Jun as a key determinant of the denervated SC phenotype creates new routes for potential therapeutic intervention/investigation. The augmentation of c-Jun triggers paracrine and autocrine loops (e.g., Shh activation) that further maintain the rSC phenotype (leading to neurotrophin secretion and morphological changes that aid nerve regeneration). Several pharmaceutical agents (fingolimod/Hh agonists/Anisomycin/HDAC inhibitors) and genetic engineering strategies have been used to directly augment c-Jun and improve experimental nerve regeneration. The use of the ASC secretome, electrical and mechanical stimuli and agonists from the growth hormone axis also modulate the rSC phenotype (likely through the modulation of c-Jun) and have been explored to the same end.