Analysis of Schwann Cell Migration and Axon Regeneration Following Nerve Injury in the Sciatic Nerve Bridge

Abstract

While it is proposed that interaction between Schwann cells and axons is key for successful nerve regeneration, the behavior of Schwann cells migrating into a nerve gap following a transection injury and how migrating Schwann cells interact with regenerating axons within the nerve bridge has not been studied in detail. In this study, we combine the use of our whole-mount sciatic nerve staining with the use of a proteolipid proteingreen fluorescent protein (PLP-GFP) mouse model to mark Schwann cells and have examined the behavior of migrating Schwann cells and regenerating axons in the sciatic nerve gap following a nerve transection injury. We show here that Schwann cell migration from both nerve stumps starts later than the regrowth of axons from the proximal nerve stump. The first migrating Schwann cells are only observed 4 days following mouse sciatic nerve transection injury. Schwann cells migrating from the proximal nerve stump overtake regenerating axons on day 5 and form Schwann cell cords within the nerve bridge by 7 days post-transection injury. Regenerating axons begin to attach to migrating Schwann cells on day 6 and then follow their trajectory navigating across the nerve gap. We also observe that Schwann cell cords in the nerve bridge are not wide enough to guide all the regenerating axons across the nerve bridge, resulting in regenerating axons growing along the outside of both proximal and distal nerve stumps. From this analysis, we demonstrate that Schwann cells play a crucial role in controlling the directionality and speed of axon regeneration across the nerve gap. We also demonstrate that the use of the PLP-GFP mouse model labeling Schwann cells together with the whole sciatic nerve axon staining technique is a useful research model to study the process of peripheral nerve regeneration.

Migrating Schwann cells direct axon regeneration within the peripheral nerve bridge

“…The rodent sciatic nerve transection has been widely used a research model to understand the molecular mechanisms of peripheral nerve regeneration after injury (Savastano et al, 2014). However, researchers in this field have experienced that, with no attempted re-suturing of the nerve ends, the lengths of the nerve gaps are variable following transection (Bozkurt et al, 2011;Cattin et al, 2015;Chen et al, 2019;Dun & Parkinson, 2018a;Parrinello et al, 2010;Savastano et al, 2014).…”

“…Following nerve transection, Schwann cells at the tips of the severed nerve stumps (i.e., distal tip of the proximal stump and proximal end of the distal stump) undergo a process of dedifferentiation, followed by proliferation and migration into the nerve gap where they form Schwann cell cords and bridge the transected nerve stumps. The formation of Schwann cell cords is key to successful peripheral nerve regeneration (Cattin et al, 2015; Chen, Chen, Parkinson, & Dun, 2019; Dun & Parkinson, 2020; Parrinello et al, 2010).…”

Electrospinning Multilayered Scaffolds Loaded with Melatonin and Fe3O4 Magnetic Nanoparticles for Peripheral Nerve Regeneration

“…[ 22 ] Based on the immunofluorescence images of S100 and NF200, regenerated axons in ML‐NGC and autograft groups were clustered and were denser than PCL‐NGC and SL‐NGC groups ( Figure A,B). The expression of S100 from ML‐NGC and SL‐NGC groups was significantly higher than PCL‐NGC group, suggesting that the addition of MLT and Fe 3 O 4 ‐MNPs enhanced Schwann cells proliferation that was essential for remyelination; [ 23 ] but there was still a large gap from autograft group (Figure 3C). Compared to autograft group, a slightly higher immunoreactivity of NF200 in SL‐NGC and ML‐NGC groups was observed, and they both performed better than PCL‐NGC group (Figure 3D).…”

FGF5 Regulates Schwann Cell Migration and Adhesion

“…Following peripheral nerve transection injury, Schwann cells from both nerve end migrate into the nerve gap and form Schwann cell cords in the nerve bridge to guide axons regeneration. This Schwann cell migration property is key to successful peripheral nerve regeneration (Parrinello et al, 2010 ; Cattin et al, 2015 ; Chen et al, 2019 ; Dun and Parkinson, 2020 ). During the period of migration in the nerve bridge, Schwann cells contact each other through their long processes and form a chain to migrate toward the middle of the nerve bridge (Chen et al, 2019 ).…”

“…This Schwann cell migration property is key to successful peripheral nerve regeneration (Parrinello et al, 2010 ; Cattin et al, 2015 ; Chen et al, 2019 ; Dun and Parkinson, 2020 ). During the period of migration in the nerve bridge, Schwann cells contact each other through their long processes and form a chain to migrate toward the middle of the nerve bridge (Chen et al, 2019 ). Schwann cell migration in the nerve bridge appears as a classic example of cell chain migration, and this chain migration is important for the correct Schwann cell cord formation in the nerve bridge (Aigouy et al, 2008 ; Parrinello et al, 2010 ; Dun and Parkinson, 2015 ).…”