The repair Schwann cell and its function in regenerating nerves

Abstract

Nerve injury triggers the conversion of myelin and non-myelin (Remak) Schwann cells to a cell phenotype specialized to promote repair. Distal to damage, these repair Schwann cells provide the necessary signals and spatial cues for the survival of injured neurons, axonal regeneration and target reinnervation. The conversion to repair Schwann cells involves de-differentiation together with alternative differentiation, or activation, a combination that is typical of cell type conversions often referred to as (direct or lineage) reprogramming. Thus, injury-induced Schwann cell reprogramming involves down-regulation of myelin genes combined with activation of a set of repair-supportive features, including up-regulation of trophic factors, elevation of cytokines as part of the innate immune response, myelin clearance by activation of myelin autophagy in Schwann cells and macrophage recruitment, and the formation of regeneration tracks, Bungner's bands, for directing axons to their targets. This repair programme is controlled transcriptionally by mechanisms involving the transcription factor c-Jun, which is rapidly up-regulated in Schwann cells after injury. In the absence of c-Jun, damage results in the formation of a dysfunctional repair cell, neuronal death and failure of functional recovery. c-Jun, although not required for Schwann cell development, is therefore central to the reprogramming of myelin and non-myelin (Remak) Schwann cells to repair cells after injury. In future, the signalling that specifies this cell requires further analysis so that pharmacological tools that boost and maintain the repair Schwann cell phenotype can be developed.

Figure 1. The repair (Bungner) Schwann cell in a developmental context

The diagram shows the repair (Bungner) Schwann cell, and the key stages of Schwann cell development, in addition to other developmental options for the Schwann cell precursor (Jessen & Mirsky, 2005). Arrows indicate developmental and injury‐related transitions. Black continuous arrows: normal development. Red arrows: the Schwann cell injury response. Dashed arrows: post‐repair re‐formation of myelin and Remak cells. Embryonic dates (E) refer to mouse development (from Jessen et al. 2015 b).

Figure 2. The structure of repair Schwann cells

A repair Schwann cell in the distal stump (4‐week transected tibial nerve without re‐innervation), as shown by serial block face scanning electron microscopy. Only a part of the cell is shown, as indicated by the box superimposed on a schematic diagram of a repair cell (R. Mirsky, K. R. Jessen H. Armer and P. Munro, unpublished).

Figure 3. Outline of myelinophagy

Left diagram: a transverse section through a myelin Schwann cell in an uninjured nerve. The myelin sheath is in direct continuity with the Schwann cell membrane and a component of the Schwann cell. Right diagram: a myelin Schwann cell after nerve injury and axonal degeneration. The myelin sheath has broken up into myelin ovoid and smaller fragments lying in the Schwann cell cytoplasm. The proposed role of autophagy in digesting these fragments is illustrated (from Gomez‐Sanchez et al. 2015).