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Molecular and cellular correlates of human nerve regeneration: ADCYAP1/PACAP enhance nerve outgrowth
We only have a rudimentary understanding of the molecular and cellular determinants of nerve regeneration and neuropathic pain in humans. This cohort study uses the most common entrapment neuropathy (carpal tunnel syndrome) as a human model system to prospectively evaluate the cellular and molecular...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462094/ https://www.ncbi.nlm.nih.gov/pubmed/32651949 http://dx.doi.org/10.1093/brain/awaa163 |
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author | Baskozos, Georgios Sandy-Hindmarch, Oliver Clark, Alex J Windsor, Katherine Karlsson, Pall Weir, Greg A McDermott, Lucy A Burchall, Joanna Wiberg, Akira Furniss, Dominic Bennett, David L H Schmid, Annina B |
author_facet | Baskozos, Georgios Sandy-Hindmarch, Oliver Clark, Alex J Windsor, Katherine Karlsson, Pall Weir, Greg A McDermott, Lucy A Burchall, Joanna Wiberg, Akira Furniss, Dominic Bennett, David L H Schmid, Annina B |
author_sort | Baskozos, Georgios |
collection | PubMed |
description | We only have a rudimentary understanding of the molecular and cellular determinants of nerve regeneration and neuropathic pain in humans. This cohort study uses the most common entrapment neuropathy (carpal tunnel syndrome) as a human model system to prospectively evaluate the cellular and molecular correlates of neural regeneration and its relationship with clinical recovery. In 60 patients undergoing carpal tunnel surgery [36 female, mean age 62.5 (standard deviation 12.2) years], we used quantitative sensory testing and nerve conduction studies to evaluate the function of large and small fibres before and 6 months after surgery. Clinical recovery was assessed with the global rating of change scale and Boston Carpal Tunnel Questionnaire. Twenty healthy participants provided normative data [14 female, mean age 58.0 (standard deviation 12.9) years]. At 6 months post-surgery, we noted significant recovery of median nerve neurophysiological parameters (P < 0.0001) and improvements in quantitative sensory testing measures of both small and large nerve fibre function (P < 0.002). Serial biopsies revealed a partial recovery of intraepidermal nerve fibre density [fibres/mm epidermis pre: 4.20 (2.83), post: 5.35 (3.34), P = 0.001], whose extent correlated with symptom improvement (r = 0.389, P = 0.001). In myelinated afferents, nodal length increased postoperatively [pre: 2.03 (0.82), post: 3.03 (1.23), P < 0.0001] suggesting that this is an adaptive phenomenon. Transcriptional profiling of the skin revealed 31 differentially expressed genes following decompression, with ADCYAP1 (encoding pituitary adenylate cyclase activating peptide, PACAP) being the most strongly upregulated (log2 fold-change 1.87, P = 0.0001) and its expression was associated with recovery of intraepidermal nerve fibres. We found that human induced pluripotent stem cell-derived sensory neurons expressed the receptor for PACAP and that this peptide could significantly enhance axon outgrowth in a dose-dependent manner in vitro [neurite length PACAP 1065.0 µm (285.5), vehicle 570.9 μm (181.8), P = 0.003]. In conclusion, carpal tunnel release is associated with significant cutaneous reinnervation, which correlates with the degree of functional improvement and is associated with a transcriptional programme relating to morphogenesis and inflammatory processes. The most highly dysregulated gene ADCYAP1 (encoding PACAP) was associated with reinnervation and, given that this peptide signals through G-protein coupled receptors, this signalling pathway provides an interesting therapeutic target for human sensory nerve regeneration. |
format | Online Article Text |
id | pubmed-7462094 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-74620942020-09-03 Molecular and cellular correlates of human nerve regeneration: ADCYAP1/PACAP enhance nerve outgrowth Baskozos, Georgios Sandy-Hindmarch, Oliver Clark, Alex J Windsor, Katherine Karlsson, Pall Weir, Greg A McDermott, Lucy A Burchall, Joanna Wiberg, Akira Furniss, Dominic Bennett, David L H Schmid, Annina B Brain Original Articles We only have a rudimentary understanding of the molecular and cellular determinants of nerve regeneration and neuropathic pain in humans. This cohort study uses the most common entrapment neuropathy (carpal tunnel syndrome) as a human model system to prospectively evaluate the cellular and molecular correlates of neural regeneration and its relationship with clinical recovery. In 60 patients undergoing carpal tunnel surgery [36 female, mean age 62.5 (standard deviation 12.2) years], we used quantitative sensory testing and nerve conduction studies to evaluate the function of large and small fibres before and 6 months after surgery. Clinical recovery was assessed with the global rating of change scale and Boston Carpal Tunnel Questionnaire. Twenty healthy participants provided normative data [14 female, mean age 58.0 (standard deviation 12.9) years]. At 6 months post-surgery, we noted significant recovery of median nerve neurophysiological parameters (P < 0.0001) and improvements in quantitative sensory testing measures of both small and large nerve fibre function (P < 0.002). Serial biopsies revealed a partial recovery of intraepidermal nerve fibre density [fibres/mm epidermis pre: 4.20 (2.83), post: 5.35 (3.34), P = 0.001], whose extent correlated with symptom improvement (r = 0.389, P = 0.001). In myelinated afferents, nodal length increased postoperatively [pre: 2.03 (0.82), post: 3.03 (1.23), P < 0.0001] suggesting that this is an adaptive phenomenon. Transcriptional profiling of the skin revealed 31 differentially expressed genes following decompression, with ADCYAP1 (encoding pituitary adenylate cyclase activating peptide, PACAP) being the most strongly upregulated (log2 fold-change 1.87, P = 0.0001) and its expression was associated with recovery of intraepidermal nerve fibres. We found that human induced pluripotent stem cell-derived sensory neurons expressed the receptor for PACAP and that this peptide could significantly enhance axon outgrowth in a dose-dependent manner in vitro [neurite length PACAP 1065.0 µm (285.5), vehicle 570.9 μm (181.8), P = 0.003]. In conclusion, carpal tunnel release is associated with significant cutaneous reinnervation, which correlates with the degree of functional improvement and is associated with a transcriptional programme relating to morphogenesis and inflammatory processes. The most highly dysregulated gene ADCYAP1 (encoding PACAP) was associated with reinnervation and, given that this peptide signals through G-protein coupled receptors, this signalling pathway provides an interesting therapeutic target for human sensory nerve regeneration. Oxford University Press 2020-07 2020-07-11 /pmc/articles/PMC7462094/ /pubmed/32651949 http://dx.doi.org/10.1093/brain/awaa163 Text en © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Baskozos, Georgios Sandy-Hindmarch, Oliver Clark, Alex J Windsor, Katherine Karlsson, Pall Weir, Greg A McDermott, Lucy A Burchall, Joanna Wiberg, Akira Furniss, Dominic Bennett, David L H Schmid, Annina B Molecular and cellular correlates of human nerve regeneration: ADCYAP1/PACAP enhance nerve outgrowth |
title | Molecular and cellular correlates of human nerve regeneration: ADCYAP1/PACAP enhance nerve outgrowth |
title_full | Molecular and cellular correlates of human nerve regeneration: ADCYAP1/PACAP enhance nerve outgrowth |
title_fullStr | Molecular and cellular correlates of human nerve regeneration: ADCYAP1/PACAP enhance nerve outgrowth |
title_full_unstemmed | Molecular and cellular correlates of human nerve regeneration: ADCYAP1/PACAP enhance nerve outgrowth |
title_short | Molecular and cellular correlates of human nerve regeneration: ADCYAP1/PACAP enhance nerve outgrowth |
title_sort | molecular and cellular correlates of human nerve regeneration: adcyap1/pacap enhance nerve outgrowth |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462094/ https://www.ncbi.nlm.nih.gov/pubmed/32651949 http://dx.doi.org/10.1093/brain/awaa163 |
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