Characterising cellular and molecular features of human peripheral nerve degeneration

Abstract

Nerve regeneration is a key biological process in those recovering from neural trauma. From animal models it is known that the regenerative capacity of the peripheral nervous system (PNS) relies heavily on the remarkable ability of Schwann cells to undergo a phenotypic shift from a myelinating phenotype to one that is supportive of neural regeneration. In rodents, a great deal is known about the molecules that control this process, such as the transcription factors c-Jun and early growth response protein 2 (EGR2/KROX20), or mark the cells and cellular changes involved, including SOX10 and P75 neurotrophin receptor (p75NTR). However, ethical and practical challenges associated with studying human nerve injury have meant that little is known about human nerve regeneration. The present study addresses this issue, analysing 34 denervated and five healthy nerve samples from 27 patients retrieved during reconstructive nerve procedures. Using immunohistochemistry and Real-Time quantitative Polymerase Chain Reaction (RT-qPCR), the expression of SOX10, c-Jun, p75NTR and EGR2 was assessed in denervated samples and compared to healthy nerve. Nonparametric smoothing linear regression was implemented to better visualise trends in the expression of these markers across denervated samples. It was found, first, that two major genes associated with repair Schwann cells in rodents, c-Jun and p75NTR, are also up-regulated in acutely injured human nerves, while the myelin associated transcription factor EGR2 is downregulated, observations that encourage the view that rodent models are relevant for learning about human nerve injury. Second, as in rodents, the expression of c-Jun and p75NTR declines during long-term denervation. In rodents, diminishing c-Jun and p75NTR levels mark the general deterioration of repair cells during chronic denervation, a process thought to be a major obstacle to effective nerve repair. The down-regulation of c-Jun and p75NTR reported here provides the first molecular evidence that also in humans, repair cells deteriorate during chronic denervation.

Development and Characterisation of an in vitro Model of Wallerian Degeneration

“…day 1 post injury but returns to normal over the 7 day time course; however, its levels are sufficient to induce persistent elevation of its protein levels which is the ultimate goal to trigger its cascade of influence in particular negative regulation of myelination and upregulation of neurotrophic factors. It is worth mentioning that upregulation of CJUN after nerve injury has been recently observed in human degenerating nerves, an observation that is comparable to our rodent in vitro model (Wilcox et al, 2020).…”

Insights Into the Role and Potential of Schwann Cells for Peripheral Nerve Repair From Studies of Development and Injury

“…As time progresses post-injury, the repair-ability of Schwann cells declines, in part due to a loss of axonal communication as nerve fibers degenerate, halting any further functional recovery (Kelsey et al, 1997 ; Arthur-Farraj et al, 2012 ; Saheb-Al-Zamani et al, 2013 ; Kumar et al, 2016 ; Poppler et al, 2016 ; Hoben et al, 2018 ; Kornfeld et al, 2019 ; Wilcox et al, 2020 ). Schwann cells thus have a limited remyelination capacity in chronically denervated distal nerves.…”

Failures of nerve regeneration caused by aging or chronic denervation are rescued by restoring Schwann cell c-Jun

“…This is an important issue in human nerve regeneration ( Ruijs et al, 2005 ) and has been studied in some detail in rats, revealing that chronic denervation results in reduced expression of repair-associated genes including Gdnf, Bdnf, Ntf3 , and Ngfr , accompanied by a dramatic reduction in the ability of denervated distal stumps to support regeneration even of freshly transected axons ( Fu and Gordon, 1995 ; You et al, 1997 ; Sulaiman and Gordon, 2000 ; Höke et al, 2002 ; Michalski et al, 2008 ; Eggers et al, 2010 ). There is direct evidence for a comparable deterioration of repair cells and repair capacity during chronic denervation of human nerves ( Wilcox et al, 2020 ; reviewed in Ruijs et al, 2005 ). Chronic denervation also results in reduced repair cell numbers and shortening of repair cells ( Benito et al, 2017 ; Gomez-Sanchez et al, 2017 ; reviewed in Jessen and Mirsky, 2019 ).…”