Accelerated re-epithelialization in β3-integrin-deficient- mice is associated with enhanced TGF-β1 signaling

Abstract

The upregulation of TGF-beta1 and integrin expression during wound healing has implicated these molecules in this process, but their precise regulation and roles remain unclear. Here we report that, notably, mice lacking beta(3)-integrins show enhanced wound healing with re-epithelialization complete several days earlier than in wild-type mice. We show that this effect is the result of an increase in TGF-beta1 and enhanced dermal fibroblast infiltration into wounds of beta(3)-null mice. Specifically, beta(3)-integrin deficiency is associated with elevated TGF-beta receptor I and receptor II expression, reduced Smad3 levels, sustained Smad2 and Smad4 nuclear localization and enhanced TGF-beta1-mediated dermal fibroblast migration. These data indicate that alpha(v)beta(3)-integrin can suppress TGF-beta1-mediated signaling, thereby controlling the rate of wound healing, and highlight a new mechanism for TGF-beta1 regulation by beta(3)-integrins.

Dermal Transforming Growth Factor-β Responsiveness Mediates Wound Contraction and Epithelial Closure

“…Previous studies have shown that mice lacking ␤ 3 integrin had accelerated re-epithelization compared with wild-type mice. 51 Reports from Grenache et al, 52 Zweers et al, 53 and Parks 54 indicated that skin develops normally in mice deficient in the ␣2-integrin subunit. In those mouse models, the authors found changes in other ␤1 integrins that may compensate for the loss of the ␣ 2 ␤ 1 integrin.…”

Integrins in Wound Healing

“…3; Table 2). [46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65] Integrins can be divided into four subfamilies based on their ligand specificity and/or phylogenetic comparison of the a subunits (Fig. 3).…”

“…94 For example, knocking out neutrophil and monocyte integrin a M b 2 delays skin wound re-epithelialization in mice; whereas elimination of a v b 3 integrin, which is expressed in wounds by platelets, endothelial cells, macrophages, and fibroblasts, accelerates it (Table 2). 50,53 The formation of a new basement membrane zone is an example where interaction between keratinocytes and fibroblasts is crucially involved, as the basement membrane components are produced jointly by the two types of cells. 94 Similarly, endothelial cells and pericytes collaborate in the assembly of vascular basement membranes during wound angiogenesis.…”

“…Notably, mice lacking b 3 integrins show faster epidermal wound healing with enhanced dermal fibroblast infiltration into wounds (Table 2). 50 Both b 1 and a v integrins are involved in myofibroblast differentiation and in granulation tissue synthesis and remodeling. About 1 week after wounding, the connective tissue cells within the wound granulation tissue start expressing alphasmooth muscle actin (aSMA) in the cytoskeletal stress fibers, becoming myofibroblasts.…”

“…140 Thicker fibers create a rigid matrix, generating more tension, which leads to cell switching to a v b 3 integrin and noncollagen ECM interactions. 140 However, fibroblast differentiation into myofibroblasts and wound contraction are not affected by a v b 3 integrin deficiency at least in the mouse skin wound healing model (Table 2), 50 suggesting that compensatory mechanisms exist in vivo.…”