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Int. J. Mol. Sci. 2018, 19(2), 604;

The Connexin Mimetic Peptide Gap27 and Cx43-Knockdown Reveal Differential Roles for Connexin43 in Wound Closure Events in Skin Model Systems

Department of Life Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow G4 0BA, UK
Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, P.O. Box 801394, Charlottesville, VA 22908, USA
Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TT, UK
Current Address: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK
Author to whom correspondence should be addressed.
Received: 19 January 2018 / Revised: 7 February 2018 / Accepted: 9 February 2018 / Published: 18 February 2018
(This article belongs to the Special Issue Interplay of Connexins and Pannexins in Tissue Function and Disease)
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In the epidermis, remodelling of Connexin43 is a key event in wound closure. However, controversy between the role of connexin channel and non-channel functions exist. We compared the impact of SiRNA targeted to Connexin43 and the connexin mimetic peptide Gap27 on scrape wound closure rates and hemichannel signalling in adult keratinocytes (AK) and fibroblasts sourced from juvenile foreskin (JFF), human neonatal fibroblasts (HNDF) and adult dermal tissue (ADF). The impact of these agents, following 24 h exposure, on GJA1 (encoding Connexin43), Ki67 and TGF-β1 gene expression, and Connexin43 and pSmad3 protein expression levels, were examined by qPCR and Western Blot respectively. In all cell types Gap27 (100–100 μM) attenuated hemichannel activity. In AK and JFF cells, Gap27 (100 nM–100 μM) enhanced scrape wound closure rates by ~50% but did not influence movement in HNDF or ADF cells. In both JF and AK cells, exposure to Gap27 for 24 h reduced the level of Cx43 protein expression but did not affect the level in ADF and HNDF cells. Connexin43-SiRNA enhanced scrape wound closure in all the cell types under investigation. In HDNF and ADF, Connexin43-SiRNA enhanced cell proliferation rates, with enhanced proliferation also observed following exposure of HDNF to Gap27. By contrast, in JFF and AK cells no changes in proliferation occurred. In JFF cells, Connexin43-SiRNA enhanced TGF-β1 levels and in JFF and ADF cells both Connexin43-SiRNA and Gap27 enhanced pSmad3 protein expression levels. We conclude that Connexin43 signalling plays an important role in cell migration in keratinocytes and foreskin derived fibroblasts, however, different pathways are evoked and in dermal derived adult and neonatal fibroblasts, inhibition of Connexin43 signalling plays a more significant role in regulating cell proliferation than cell migration. View Full-Text
Keywords: wound healing; connexin mimetic peptide; connexin hemichannel; cell migration; SiRNA wound healing; connexin mimetic peptide; connexin hemichannel; cell migration; SiRNA

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Faniku, C.; O’Shaughnessy, E.; Lorraine, C.; Johnstone, S.R.; Graham, A.; Greenhough, S.; Martin, P.E. The Connexin Mimetic Peptide Gap27 and Cx43-Knockdown Reveal Differential Roles for Connexin43 in Wound Closure Events in Skin Model Systems. Int. J. Mol. Sci. 2018, 19, 604.

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