ILK–PI3K/AKT pathway participates in cutaneous wound contraction by regulating fibroblast migration and differentiation to myofibroblast

• Published in: Laboratory investigation 2016-07, Vol.96 (7), p.741-751
• Main Authors: Li, Gang, Li, Ye-Yang, Sun, Jing-En, Lin, Wei-hua, Zhou, Ri-xing
• Format: Article
• Language: English
• Subjects: 13/1; 13/95; 64/60; 692/699/578; 96/2; 96/63; 96/98; Actins - metabolism; Animals; Azo Compounds - pharmacology; Cell Differentiation - drug effects; Cell Movement - drug effects; Cells, Cultured; Chromones - pharmacology; Collagen - metabolism; Female; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - pathology; Humans; Laboratory Medicine; Medicine; Medicine & Public Health; Morpholines - pharmacology; Myofibroblasts - drug effects; Myofibroblasts - metabolism; Myofibroblasts - pathology; Pathology; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors - pharmacology; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Pyrazoles - pharmacology; Rats; Rats, Sprague-Dawley; research-article; RNA, Small Interfering - genetics; Signal Transduction - drug effects; Skin - injuries; Skin - metabolism; Skin - pathology; Transforming Growth Factor beta1 - metabolism; Wound Healing - drug effects; Wound Healing - genetics; Wound Healing - physiology
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/labinvest.2016.48

The interactions between fibroblasts and the extracellular matrix in wound contraction are mainly mediated via integrin signaling. Integrin-linked kinase (ILK) is a key mediator in integrin signal transduction. We investigated the role of ILK in cutaneous wound contraction. We found that ILK was involved in cutaneous wound healing in rats, and ILK and PI3K/AKT inhibitors inhibited wound contraction and re-epithelialization, consequently delaying wound healing in vivo. Further, using in vitro studies, we demonstrated that ILK and PI3K/AKT inhibitors suppressed the contraction of fibroblast-populated collagen lattices, inhibited fibroblast migration, and interrupted the effect of TGF-β1 on promoting alpha smooth muscle actin (α-SMA) expression in fibroblasts. When ILK expression was directly blocked by ILK small interfering RNA transfection, the migration and α-SMA expression of normal dermal fibroblasts were significantly suppressed as well. The data suggest that the ILK–PI3K/AKT signaling pathway mediates cutaneous wound contraction by regulating fibroblast migration and differentiation to myofibroblasts.