Cell motility in models of wounded human skin is improved by Gap27 despite raised glucose, insulin and IGFBP-5

• Published in: Experimental cell research 2013-02, Vol.319 (4), p.390-401
• Main Authors: Wright, Catherine S., Berends, Rebecca F., Flint, David J., Martin, Patricia E.M.
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Cell adhesion & migration; Cell Culture Techniques; Cell Migration Assays; Cell Movement - drug effects; Cell Movement - physiology; CELL PROLIFERATION; Cells, Cultured; Connexin; Connexins - pharmacology; Dose-Response Relationship, Drug; GLUCOSE; Glucose - pharmacology; GROWTH FACTORS; Humans; IGF; Infant, Newborn; INSULIN; Insulin - pharmacology; Insulin-Like Growth Factor Binding Protein 5 - pharmacology; Keratinocyte; Keratinocytes - cytology; Keratinocytes - drug effects; Models, Theoretical; Osmolar Concentration; Peptide; PEPTIDES; SKIN; Skin Physiological Phenomena - drug effects; Up-Regulation - drug effects; Wound; Wound healing; Wound Healing - drug effects; WOUNDS
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2012.12.013

Reducing Cx43 expression stimulates skin wound healing. This is mimicked in models when Cx43 function is blocked by the connexin mimetic peptide Gap27. IGF-I also stimulates wound healing with IGFBP-5 attenuating its actions. Further, the IGF-I to IGFBP-5 ratio is altered in diabetic skin, where wound closure is impaired. We investigated whether Gap27 remains effective in augmenting scrape-wound closure in human skin wound models simulating diabetes-induced changes, using culture conditions with raised glucose, insulin and IGFBP-5. Gap27 increased scrape-wound closure in normal glucose and insulin (NGI) and to a lesser extent in high glucose and insulin (HGI). IGF-I enhanced scrape-wound closure in keratinocytes whereas IGFBP-5 inhibited this response. Gap27 overcame the inhibitory effects of IGFBP-5 on IGF-I activity. Connexin-mediated communication (CMC) was reduced in HGI, despite raised Cx43, and Gap27 significantly decreased CMC in NGI and HGI. IGF-I and IGFBP-5 did not affect CMC. IGF-I increased keratinocyte proliferation in NGI, and Gap27 increased proliferation in NGI to a greater extent than in HGI. We conclude that IGF-I and Gap27 stimulate scrape-wound closure by independent mechanisms with Gap27 inhibiting Cx43 function. Gap27 can enhance wound closure in diabetic conditions, irrespective of the IGF-I:IGFBP-5 balance. ► Human organotypic and keratinocyte ‘diabetic’ skin models were used to demonstrate the ability of Gap27 to improve scrape-wound closure. ► Gap27 enhanced scrape-wound closure by reducing Cx43-mediated communication, whereas IGFBP-5 retarded cell migration. ► IGF-I and IGFBP-5 did not affect connexin-mediated pathways. ► Gap27 can override altered glucose, insulin, IGF-I, and IGFBP-5 in ‘diabetic’ skin models and thus has therapeutic potential.