Integrin-mediated regulation of epidermal wound functions

Abstract

During cutaneous wound healing, keratinocyte proliferation and migration are critical for re-epithelialization. In addition the epidermis secretes growth factors, cytokines, proteases, and matricellular proteins into the wound microenvironment that modify the extracellular matrix and stimulate other wound cells that control the inflammatory response, promote angiogenesis and facilitate tissue contraction and remodeling. Wound keratinocytes express at least seven different integrins-the major cell adhesion receptors for the extracellular matrix-that collectively control essential cell-autonomous functions to ensure proper re-epithelialization, including migration, proliferation, survival and basement membrane assembly. Moreover, it has become evident in recent years that some integrins can regulate paracrine signals from wound epidermis that stimulate other wound cells involved in angiogenesis, contraction and inflammation. Importantly, it is likely that abnormal integrin expression or function in the epidermis contributes to wound pathologies such as over-exuberant healing (e.g., hypertrophic scar formation) or diminished healing (e.g., chronic wounds). In this review, we discuss current knowledge of integrin function in the epidermis, which implicates them as attractive therapeutic targets to promote wound healing or treat wound pathologies. We also discuss challenges that arise from the complex roles that multiple integrins play in wound epidermis, which may be regulated through extracellular matrix remodeling that determines ligand availability. Indeed, understanding how different integrin functions are temporally coordinated in wound epidermis and which integrin functions go awry in pathological wounds, will be important to determine how best to target them clinically to achieve maximum therapeutic benefit. Graphical abstract In addition to their well-characterized roles in keratinocyte adhesion, migration and wound re-epithelialization, epidermal integrins play important roles in modifying the wound microenvironment by regulating the expression and secretion of growth factors, extracellular proteases, and matricellular proteins that stimulate other wound cells, including vascular endothelial cells and fibroblasts/myofibroblasts.

Keywords: Epidermis; Extracellular matrix; Integrin; Keratinocyte; Wound healing.

Fig. 1

Illustration depicts functions of wound epidermis that may be controlled by keratinocyte integrins. Arrow 1 indicates wound re-epithelialization, which is driven by keratinocyte proliferation, local matrix remodeling, and migration. Arrow 2 indicates paracrine signaling from the epidermis to vascular endothelial cells that promotes wound angiogenesis. Arrow 3 indicates paracrine signaling from the epidermis to other wound cells, including inflammatory cells (blue cells) and fibroblasts/myofibroblasts that promote wound contraction (green cells). The wound bed is indicated in red-to-pink gradient.