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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 fibroblastpopulated collagen lattices, inhibited fibroblast migration, and interrupted the effect of TGF-β 1 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.

Therapeutic study, level III.

Wound healing is a multicellular process that involves the coordinated efforts of several cell types, including keratinocytes, fibroblasts, and endothelial cells. This process is also regulated by an equally complex signaling network involving numerous growth factors, cytokines, and chemokines. The mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of cell growth, proliferation, and differentiation. A recent study showed that mTORC1 activation in epithelial cells dramatically enhanced epithelial cell proliferation, migration, and cutaneous wound healing; however, the roles of mTORC1 in fibroblasts during wound healing remain unknown. Here, we generated genetically mutated mice with activated mTORC1 in fibroblasts by conditionally deleting the mTORC1 inhibitor, TSC1. Activation of mTORC1 in fibroblasts significantly increased fibroblastic cell proliferation and contractile α‐smooth muscle actin expression, thus promoting wound closure. Elevated mTORC1 activity also adversely induced excessive collagen production, leading to excessive scaring and fibrosis. Importantly, both accelerated wound healing and fibrotic phenotypes were largely reversed by the mTORC1 inhibitor, rapamycin. These observations were also replicated in primary human dermal fibroblasts. These results collectively demonstrated that mTORC1 activity in skin fibroblasts was a critical orchestrator in cutaneous wound healing and scarring.