Molecular and cellular correlates of human nerve regeneration: ADCYAP1/PACAP enhance nerve outgrowth

Baskozos, G. et al. (2020) Molecular and cellular correlates of human nerve regeneration: ADCYAP1/PACAP enhance nerve outgrowth. Brain, 143(7), pp. 2009-2026. (doi: 10.1093/brain/awaa163) (PMID:32651949) (PMCID:PMC7462094)

Abstract

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.

• Item Type: Articles
• Additional Information: This work was supported by the NIHR Biomedical Research Centre, Oxford. A.B.S. was funded by an advanced postdoc mobility Fellowship from the Swiss National Science Foundation (P00P3-158835) and received project funding from the early career research grant awarded by the International Association for the Study of Pain. D.L.B. is a Wellcome senior clinical scientist (ref. no. 095698z/11/z and 202747/Z/16/Z) and is supported by the Wellcome Trust Pain Consortium Strategic Award. O.S.H. is supported by a studentship from Immunocore Ltd. A.J.C. is supported by a non-clinical fellowship from Guarantors of Brain. L.A.M. is funded by a BBSRC grant (BB/S006788/1). P.K. is a member of the International Diabetic Neuropathy Consortium (IDNC) research programme, which is supported by a Novo Nordisk Foundation Challenge Programme grant (Grant number NNF14OC0011633) and is additionally funded by a grant from the Novo Nordisk Foundation (Grant number NNF18OC0052301). D.F. was supported by an Intermediate Clinical Fellowship from the Wellcome Trust (097152/Z/11/Z).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Weir, Dr Gregory
• Authors: Baskozos, G., Sandy-Hindmarch, O., Clark, A. J., Windsor, K., Karlsson, P., Weir, G. A., McDermott, L. A., Burchall, J., Wiberg, A., Furniss, D., Bennett, D. L.H., and Schmid, A. B.
• College/School: College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
• Journal Name: Brain
• Publisher: Oxford University Press
• ISSN: 0006-8950
• ISSN (Online): 1460-2156
• Published Online: 11 July 2020
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in Brian 143(7): 2009-2026
• Publisher Policy: Reproduced under a Creative Commons License