Abstract

While Nogo protein demonstrably inhibits nerve regeneration in the central nervous system (CNS), its effect on Schwann cells in peripheral nerve repair and regeneration following sciatic nerve injury remains unknown. In this research, We assessed the post-injury expression of Nogo-C in an experimental mouse model of sciatic nerve-crush injury. Nogo-C knockout (Nogo-C–/–) mouse was generated to observe the effect of Nogo-C on sciatic nerve regeneration, Schwann cell apoptosis, and myelin disintegration after nerve injury, and the effects of Nogo-C on apoptosis and dedifferentiation of Schwann cells were observed in vitro. We found that the expression of Nogo-C protein at the distal end of the injured sciatic nerve increased in wild type (WT) mice. Compared with the injured WT mice, the proportion of neuronal apoptosis was significantly diminished and the myelin clearance rate was significantly elevated in injured Nogo-C–/– mice; the number of nerve fibers regenerated and the degree of myelination were significantly elevated in Nogo-C–/– mice on Day 14 after injury. In addition, the recovery of motor function was significantly accelerated in the injured Nogo-C–/– mice. The overexpression of Nogo-C in primary Schwann cells using adenovirus-mediated gene transfer promoted Schwann cells apoptosis. Nogo-C significantly reduced the ratio of c-Jun/krox-20 expression, indicating its inhibition of Schwann cell dedifferentiation. Above all, we hold the view that the expression of Nogo-C increases following peripheral nerve injury to promote Schwann cell apoptosis and inhibit Schwann cell dedifferentiation, thereby inhibiting peripheral nerve regeneration.

Highlights

  • Peripheral nerve injury is a common type of trauma, leading to limb paralysis and limited activity, which may impose a heavy social and economic burden on patients (Abrams and Widenfalk, 2005; Hoke, 2006; Navarro et al, 2007)

  • Nogo-C expression increased in the distal end of the injured sciatic nerve in mice, suggesting that Nogo-C may be involved in peripheral nerve repair

  • The results from our study suggest that Nogo-C is closely related to peripheral nerve repair after peripheral nerve injury, as evidenced by the following findings: (1) Nogo-C expression was increased in the distal end of the injured sciatic nerve; (2) Nogo-C knockout accelerated the repair of injured sciatic nerve and reduced the number of apoptotic cells in the injured nerve lesions; and (3) overexpression of Nogo-C simultaneously promoted Schwann cell apoptosis and inhibition of dedifferentiation

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Summary

Introduction

Peripheral nerve injury is a common type of trauma, leading to limb paralysis and limited activity, which may impose a heavy social and economic burden on patients (Abrams and Widenfalk, 2005; Hoke, 2006; Navarro et al, 2007). Schwann cells play a central role (Huang et al, 2016) in nerve regeneration; they undergo cell reprogramming during Wallerian degeneration (Armstrong et al, 2007; Campana, 2007; Webber and Zochodne, 2010; Allodi et al, 2012) and transform from mature and differentiated myelinating Schwann cells into repairing Schwann cells (Arthur-Farraj et al, 2012, 2017; Jessen and Arthur-Farraj, 2019) In this process, Schwann cells reverse their myelin differentiation. While a large number of genes related to myelination are downregulated, including P0, myelin basic protein (MBP), and membrane associated proteins such as myelin associated glycoprotein (MAG) and periaxin This type of Schwann cell plays an important role in promoting axonal regeneration. Schwann cells with phenotypic transition after nerve injury are involved in the repair of injured nerves via various pathways

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