Irreversible changes occurring in long-term denervated Schwann cells affect delayed nerve repair

Abstract

OBJECTIVE Multiple factors may affect functional recovery after peripheral nerve injury, among them the lesion site and the interval between the injury and the surgical repair. When the nerve segment distal to the lesion site undergoes chronic degeneration, the ensuing regeneration (when allowed) is often poor. The aims of the current study were as follows: 1) to examine the expression changes of the neuregulin 1/ErbB system during long-term nerve degeneration; and 2) to investigate whether a chronically denervated distal nerve stump can sustain nerve regeneration of freshly axotomized axons. METHODS This study used a rat surgical model of delayed nerve repair consisting of a cross suture between the chronically degenerated median nerve distal stump and the freshly axotomized ulnar proximal stump. Before the suture, a segment of long-term degenerated median nerve stump was harvested for analysis. Functional, morphological, morphometric, and biomolecular analyses were performed. RESULTS The results showed that neuregulin 1 is highly downregulated after chronic degeneration, as well as some Schwann cell markers, demonstrating that these cells undergo atrophy, which was also confirmed by ultrastructural analysis. After delayed nerve repair, it was observed that chronic degeneration of the distal nerve stump compromises nerve regeneration in terms of functional recovery, as well as the number and size of regenerated myelinated fibers. Moreover, neuregulin 1 is still downregulated after delayed regeneration. CONCLUSIONS The poor outcome after delayed nerve regeneration might be explained by Schwann cell impairment and the consequent ineffective support for nerve regeneration. Understanding the molecular and biological changes occurring both in the chronically degenerating nerve and in the delayed nerve repair may be useful to the development of new strategies to promote nerve regeneration. The results suggest that neuregulin 1 has an important role in Schwann cell activity after denervation, indicating that its manipulation might be a good strategy for improving outcome after delayed nerve repair.

Polycomb repression regulates Schwann cell proliferation and axon regeneration after nerve injury

“…We speculate the normal demethylation of H3K27, at least in young mice, may be sufficient to drive expression of adequate amounts of critical nerve repair genes. However, the ultrastructural analysis revealed that the function of Schwann cell EED is critical for timely axon regeneration, a function likely to be critical for efficient nerve regeneration since the survival and capacity of Schwann cells decrease at more distal sites that are chronically denervated (Benito et al 2017; Eggers et al 2010; Höke et al 2002; Jessen and Mirsky 1999; Jonsson et al 2013; Li et al 1997; Michalski et al 2008; Ronchi et al 2017; Sulaiman and Gordon 2009). …”

“…Despite the striking adaptability of Schwann cells to damage, the clinical outcomes of human patients generally exhibit only partial recovery in many cases (Höke, 2006;Lundborg, 2000). One of the main reasons is that axons must regenerate over a relatively long distance, and Schwann cells more distal to injury sites gradually lose their ability to foster nerve regeneration (Jonsson et al, 2013;Ronchi et al, 2017;Sulaiman & Gordon, 2009;Sulaiman & Gordon, 2013), which could be in part due to reduced expression of neurotrophic factors like GDNF and BDNF (Eggers, Tannemaat, Ehlert, & Verhaagen, 2010;Fontana et al, 2012;Höke, Gordon, Zochodne, & Sulaiman, 2002;Li, Terenghi, & Hall, 1997;Michalski, Bain, & Fahnestock, 2008;Sulaiman & Gordon, 2009). Therefore, identifying the molecular mechanisms that enable rapid axon regeneration is important for improving therapeutic strategies for peripheral nerve damage.…”

Comparative Evaluation of Chitosan Nerve Guides with Regular or Increased Bendability for Acute and Delayed Peripheral Nerve Repair: A Comprehensive Comparison with Autologous Nerve Grafts and Muscle‐in‐Vein Grafts

“…Especially in multi trauma patients with complex wounds that have to be cured with priority (Evriviades et al, ; Moore et al, ), nerve reconstruction might be delayed for up to several weeks. Although the functional outcome will be decreased due to a progressive downregulation in the expression of regeneration‐associated genes by chronically axotomized axons and long‐term denervated Schwann cells (Gordon and Tetzlaff, ; Ronchi et al, ; Ronchi and Raimondo, ), postponed nerve reconstruction is still advised. Nevertheless, also patients that were treated immediately following severe peripheral nerve lesions usually suffer from life‐long symptoms since functional recovery often remains incomplete (Deumens et al, ).…”

Restoration of Neurological Function Following Peripheral Nerve Trauma

“…When anastomosis is performed within 14 days of nerve trauma, functional recovery is good in about 80% of patients [37]. However, with increasing time between nerve trauma and anastomosis, the extent of recovery decreases [38][39][40]. The types of changes that occur over time that lead to this decrease in recovery are discussed below.…”

“…Another explanation for the significant decrease in axon regeneration with increasing time of motor neuron axotomy is that many motor neurons lose the ability to extend axons [83]. The decrease in the ability of motor neurons to regenerate with increasing time of axotomy appears to be associated with the downregulation of neuregulin 1, which is required for axon regeneration [38,84,85]. However, it is important to note that while some motor neurons lose this capacity, others can regenerate even after many years of axotomy.…”