The Success and Failure of the Schwann Cell Response to Nerve Injury

Abstract

The remarkable plasticity of Schwann cells allows them to adopt the Remak (non-myelin) and myelin phenotypes, which are specialized to meet the needs of small and large diameter axons, and differ markedly from each other. It also enables Schwann cells initially to mount a strikingly adaptive response to nerve injury and to promote regeneration by converting to a repair-promoting phenotype. These repair cells activate a sequence of supportive functions that engineer myelin clearance, prevent neuronal death, and help axon growth and guidance. Eventually, this response runs out of steam, however, because in the long run the phenotype of repair cells is unstable and their survival is compromised. The re-programming of Remak and myelin cells to repair cells, together with the injury-induced switch of peripheral neurons to a growth mode, gives peripheral nerves their strong regenerative potential. But it remains a challenge to harness this potential and devise effective treatments that maintain the initial repair capacity of peripheral nerves for the extended periods typically required for nerve repair in humans.

Keywords: PNS; Schwann cell; c-Jun; nerve injury; re-programming; regeneration; repair cell.

Figure 1

Diagrammatic representation of uninjured and injured nerve. Each diagram shows one fascicle and its main cellular constituents. Red line: basal lamina of Schwann cells (the basal lamina associated with perineurium and blood vessels is not shown), P, perineurium; R, Remak Schwann cell; M, myelin Schwann cell; F, fibroblast; E the connective tissue of the endoneurium, Ma, macrophage; BB, Bungner band containing transverse profiles of several repair cells and surrounded by a basal lamina.

Figure 2

The main transitions in the Schwann cell lineage during development and after injury. Black uninterrupted arrows show normal development. Red arrows show the Schwann cell injury response. Black stippled arrows show post-repair reformation of Remak and myelin cells (with permission from Jessen et al., 2015b).

Figure 3

Main cell and tissue components of regenerating nerves. Repair cells in Bungner bands are shown in dark orange (e). Light blue shows the Schwann cells of the tissue bridge, some of which migrate out from the distal stump (c), while others accompany regenerating axons forming regeneration units (a). Not shown is the basal lamina that covers the Schwann cells in the proximal stump and the Bungner bands in the distal stump. The bridge Schwann cells receive important signals from blood vessels (b), fibroblasts and macrophages (d). The position of an inserted regeneration conduit is also shown (although the cellular events within it will depend on the nature of the conduit; with permission from Jessen and Arthur-Farraj, 2019).

Figure 4

Myelin, Remak and repair Schwann cells after genetic labeling in vivo. Shown in green are myelin and Remak cells of average length as they appear in uninjured nerve. In red is an example of a long, branched repair cell (generated from a myelin cell), in 4 week cut nerve without reinnervation. All cells are shown to scale. Shown also is a schematic diagram of a repair cell and the assembly of these cells to form a Bungner band enclosed by a basal lamina and containing a regenerating axon (in blue). The electron micrograph shows a transverse section of a Bungner band (red image printed with permission from Gomez-Sanchez et al., 2017). Scale bar: 1 μm.

Figure 5

The structure of regeneration tracks (Bungner Bands) is controlled by Schwann cell c-Jun. Electron micrographs from the distal stump of mouse sciatic nerve 4 weeks after transection (without regeneration). (A) WT nerve showing classic regeneration tracks (Bands of Bungner; an example is arrowed). (B) Distorted regeneration tracks in c-Jun cKO nerve, containing irregular and flattened cellular profiles (with permission from Arthur-Farraj et al., 2012). Scale bar: 1 μm.