Transection injury differentially alters the proteome of the human sural nerve

Abstract

Regeneration after severe peripheral nerve injury is often poor. Knowledge of human nerve regeneration and the growth microenvironment is greatly lacking. We aimed to identify the regenerative proteins in human peripheral nerve by comparing the proteome before and after a transection injury. In a unique study design, we collected closely matched samples of naïve and injured sural nerve. Naïve and injured (two weeks after injury) samples were analyzed using mass spectrometry and immunoassays. We found significantly altered levels following the nerve injury. Mass spectrometry revealed that injury samples had 568 proteins significantly upregulated and 471 significantly downregulated compared to naïve samples (q-value ≤ 0.05 and Z ≥ |2| (log2)). We used Gene Ontology (GO) pathway overrepresentation analysis to highlight groups of proteins that were significantly upregulated or downregulated with injury-induced degeneration and regeneration. Significant protein changes in key pathways were identified including growth factor levels, Schwann cell de-differentiation, myelination downregulation, epithelial-mesenchymal transition (EMT), and axonal regeneration pathways. The proteomes of the uninjured nerve compared to the degenerating/regenerating nerve may reveal biomarkers to aid in the development of repair strategies such as infusing supplemental trophic factors and in monitoring neural tissue regeneration.

Research progress on the reduced neural repair ability of aging Schwann cells

“…Besides, SCs transdifferentiated or reprogrammed from a mature form into a repair phenotype. Chau et al (2022) reached a similar conclusion in a study of transection injury to the human sural nerve.…”

Proximity proteomics reveals role of Abelson interactor 1 in the regulation of TAK1/RIPK1 signaling

“…TMT proteomics and data analyses were performed as previously described [ 46 , 47 ]. Proteins from flash‐frozen cell pellets (1e6 cells per pellet, n = 3 per cell line) were reduced, alkylated, and purified by chloroform/methanol extraction prior to digestion with sequencing grade modified porcine trypsin (Promega, Madison, WI, USA).…”

The Dynamics of Nerve Degeneration and Regeneration in a Healthy Milieu and in Diabetes

“…Most studies of the early and late responses of Schwann cells and other central players in the nerve degeneration and regeneration processes have focused on the events in animals. Few studies have studied the protein response in injured human peripheral nerves [133][134][135] or in humans with type 1 and type 2 diabetes [85,136]. It has been reported that two major genes, associated with repair Schwann cells, c-Jun and p75 NTR , are up-regulated in injured human nerves in healthy subjects, while the myelin-associated transcription factor (EGR2) is down-regulated [135].…”

“…It has been reported that two major genes, associated with repair Schwann cells, c-Jun and p75 NTR , are up-regulated in injured human nerves in healthy subjects, while the myelin-associated transcription factor (EGR2) is down-regulated [135]. In a proteomics study of the sural nerve that was subjected to a nerve injury (surgery in patients with idiopathic Parkinson's disease in connection with nerve grafting into substantia nigra; control nerve and then distal nerve end harvested at two weeks follow up; age 50-70 years), 8/20 most prominently up-regulated pathways were associated with gene expression through translation, while the top down-regulated pathways were associated with cytoskeletal organization or structure as well as to neuron and synapses [133]. Detailed changes were reported concerning growth factors (e.g., glial cell-derived neurotrophic factor; GDNF, brain-derived neurotrophic factor; BDNF; transforming growth factor-β; TGF-β and VEGF), myelination, Schwann cell differentiation (e.g., c-Jun), regulation of apoptotic processes, and response to "axonal injury" [133,137].…”

“…In a proteomics study of the sural nerve that was subjected to a nerve injury (surgery in patients with idiopathic Parkinson's disease in connection with nerve grafting into substantia nigra; control nerve and then distal nerve end harvested at two weeks follow up; age 50-70 years), 8/20 most prominently up-regulated pathways were associated with gene expression through translation, while the top down-regulated pathways were associated with cytoskeletal organization or structure as well as to neuron and synapses [133]. Detailed changes were reported concerning growth factors (e.g., glial cell-derived neurotrophic factor; GDNF, brain-derived neurotrophic factor; BDNF; transforming growth factor-β; TGF-β and VEGF), myelination, Schwann cell differentiation (e.g., c-Jun), regulation of apoptotic processes, and response to "axonal injury" [133,137]. The expression of the previously mentioned genes declines during a long-term denervation in accordance with an observed impaired regeneration over time after a nerve injury in experimental animals [49][50][51]122,135,138,139].…”