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

Author:

Baskozos Georgios1,Sandy-Hindmarch Oliver1,Clark Alex J1,Windsor Katherine1,Karlsson Pall2,Weir Greg A13,McDermott Lucy A1,Burchall Joanna4,Wiberg Akira4ORCID,Furniss Dominic4,Bennett David L H1,Schmid Annina B1ORCID

Affiliation:

1. Nuffield Department of Clinical Neurosciences, The University of Oxford, Oxford, UK

2. Department of Clinical Medicine, The Danish Pain Research Center, Aarhus, Denmark

3. Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK

4. Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, The University of Oxford, Oxford, UK

Abstract

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.

Funder

NIHR

Biomedical Research Centre

Swiss National Science Foundation

International Association for the Study of Pain

Wellcome Trust

BBSRC

International Diabetic Neuropathy Consortium

IDNC

Novo Nordisk Foundation Challenge Programme

Novo Nordisk Foundation

NHS

Department of Health

Publisher

Oxford University Press (OUP)

Subject

Neurology (clinical)

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