Repair Schwann cell update: Adaptive reprogramming, EMT, and stemness in regenerating nerves

Abstract

Schwann cells respond to nerve injury by cellular reprogramming that generates cells specialized for promoting regeneration and repair. These repair cells clear redundant myelin, attract macrophages, support survival of damaged neurons, encourage axonal growth, and guide axons back to their targets. There are interesting parallels between this response and that found in other tissues. At the cellular level, many other tissues also react to injury by cellular reprogramming, generating cells specialized to promote tissue homeostasis and repair. And at the molecular level, a common feature possessed by Schwann cells and many other cells is the injury‐induced activation of genes associated with epithelial–mesenchymal transitions and stemness, differentiation states that are linked to cellular plasticity and that help injury‐induced tissue remodeling. The number of signaling systems regulating Schwann cell plasticity is rapidly increasing. Importantly, this includes mechanisms that are crucial for the generation of functional repair Schwann cells and nerve regeneration, although they have no or a minor role elsewhere in the Schwann cell lineage. This encourages the view that selective tools can be developed to control these particular cells, amplify their repair supportive functions and prevent their deterioration. In this review, we discuss the emerging similarities between the injury response seen in nerves and in other tissues and survey the transcription factors, epigenetic mechanisms, and signaling cascades that control repair Schwann cells, with emphasis on systems that selectively regulate the Schwann cell injury response.

Schwann cells orchestrate peripheral nerve inflammation through the expression of CSF1, IL‐34, and SCF in amyotrophic lateral sclerosis

“…SCs in human and SOD1 G93A rat ALS sciatic nerves displayed remarkably similar phenotypic features, suggesting a conserved and stereotyped glial response to motor axon degeneration. SCs are regarded as key players in repair following nerve injury through the upregulation of cytokines and trophic factors (Jessen & Arthur‐Farraj, ; Jessen & Mirsky, ). SCs in ALS expressed significant levels of CSF1, IL‐34, and SCF and spatially interacted with immune effector cells bearing CSF‐1R and c‐Kit, suggesting a complex cellular interplay leading to local inflammation.…”

“…It is known that SCs follow a profound phenotypic remodeling after nerve injury allowing repair and axonal growth (Gomez‐Sanchez et al, ; Jessen & Arthur‐Farraj, ). In ALS‐affected nerves from patients with advanced paralysis and several years of disease progression, we found a comparable reactivity of SCs together with immune cell infiltration, suggesting SCs chronically retain pro‐inflammatory features.…”

Evidence for cell‐contact factor involvement in neurite outgrowth of dorsal root ganglion neurons stimulated by Schwann cells

“…Although PNS axons can regenerate, clinical outcomes after injury are devastating, especially in proximal and defective injuries (Evans, Midha, & Mackinnon, ; Lundborg, ; Seddon, ; Seddon, ). Schwann cells play an important role in axonal regeneration (Jessen & Arthur‐Farraj, ), and implantation of SCs has already been tested in the clinic (Gersey et al., ). To develop a new therapy to enhance axonal regeneration in the PNS, the detailed molecular mechanisms of SC–axon interaction need to be elucidated.…”

Schwann cell plasticity‐roles in tissue homeostasis, regeneration, and disease

“…In both environments, SCs play a critical role in orchestrating the regenerative process. This involves a remarkable reprogramming process in which quiescent and highly specialized adult SCs dedifferentiate en masse to proliferating, progenitor‐like SCs, which orchestrate the regenerative response, with distinct roles in the different regions of the nerve (Cattin & Lloyd, ; Jessen & Arthur‐Farraj, ). Lineage‐analysis of adult mSCs following injury, demonstrated the efficiency of this process with all mSCs downstream of the injury re‐entering the cell cycle within days of an injury (Stierli et al, ; Figure ).…”

“…The initiating signal from the damaged axons remains unknown but leads to a strong sustained signal through the ERK‐signaling pathway, lasting several days, which has been shown to be sufficient to drive the reprogramming process (Napoli et al, ). Whilst some positive and negative regulators of this process have been identified (reviewed in (Jessen & Arthur‐Farraj, )), the mechanistic pathways responsible for the reprogramming process remains poorly understood.…”