Interaction between Schwann cells and other cells during repair of peripheral nerve injury

Abstract

Peripheral nerve injury (PNI) is common and, unlike damage to the central nervous system injured nerves can effectively regenerate depending on the location and severity of injury. Peripheral myelinating glia, Schwann cells (SCs), interact with various cells in and around the injury site and are important for debris elimination, repair, and nerve regeneration. Following PNI, Wallerian degeneration of the distal stump is rapidly initiated by degeneration of damaged axons followed by morphologic changes in SCs and the recruitment of circulating macrophages. Interaction with fibroblasts from the injured nerve microenvironment also plays a role in nerve repair. The replication and migration of injury-induced dedifferentiated SCs are also important in repairing the nerve. In particular, SC migration stimulates axonal regeneration and subsequent myelination of regenerated nerve fibers. This mobility increases SC interactions with other cells in the nerve and the exogenous environment, which influence SC behavior post-injury. Following PNI, SCs directly and indirectly interact with other SCs, fibroblasts, and macrophages. In addition, the inter- and intracellular mechanisms that underlie morphological and functional changes in SCs following PNI still require further research to explain known phenomena and less understood cell-specific roles in the repair of the injured peripheral nerve. This review provides a basic assessment of SC function post-PNI, as well as a more comprehensive evaluation of the literature concerning the SC interactions with macrophages and fibroblasts that can influence SC behavior and, ultimately, repair of the injured nerve.

Keywords: Schwann cell migration; axon regeneration; cell-cell interactions; nerve injury; nerve repair; peripheral nerve; recovery; regeneration; repair.

Figure 1

Schematic showing the general sequence of events following PNI involving fibroblasts, macrophages, and SCs to promote SC migration and nerve repair. (A) Example of injury to a motor nerve projecting from the ventral horn of the spinal cord to target muscle tissue in the periphery. The cell body is located in the spinal cord, while the SC myelinated axon projects toward a target, where it synapses and initiates its action. (B) Nerve injury damages the integrity of the peripheral axon and induces Wallerian degeneration. (C) In response to injury, debris clearance and repair is initiated by activated SCs, recruited macrophages, and disrupted fibroblasts. Paracrine signaling involving MCP-1, LIF-1, and FGF-9 that is secreted from these cells facilitates a multicellular response to the injured nerve. (D) There is a fibroblast influence on SC behavior, which is partly mediated through direct binding of TNC to SC-expressed β1 integrin. Likewise, microvesicles released by activated macrophages also affect SC function in the repair process and depend on the inflammatory status of macrophages recruited to the injury site. (E) These cellular interactions contribute to the promotion of SC establishment of a bridge across the injury site for supporting axon regeneration and eventual myelination. (F) A repaired and regenerated peripheral nerve. FGF-9: Fibroblast growth factor 9; LIF-1: leukemia inhibitory factor-1; MCP-1: monocyte chemoattractant protein-1; PNI: peripheral nerve injury; SC: Schwann cell; TNC: tenascin-C.