The Role of the Fibronectin Synergy Site for Skin Wound Healing

Skin is constantly exposed to injuries that are repaired with different outcomes, either regeneration or scarring. Scars result from fibrotic processes modulated by cellular physical forces transmitted by integrins. Fibronectin (FN) is a major component in the provisional matrix assembled to repair skin wounds. FN enables cell adhesion binding of alpha 5 beta 1/alpha IIb beta 3 and alpha v-class integrins to an RGD-motif. An additional linkage for alpha 5/alpha II is the synergy site located in close proximity to the RGD motif. The mutation to impair the FN synergy region (Fn1(syn/syn)) demonstrated that its absence permits complete development. However, only with the additional engagement to the FN synergy site do cells efficiently resist physical forces. To test how the synergy site-mediated adhesion affects the course of wound healing fibrosis, we used a mouse model of skin injury and in-vitro migration studies with keratinocytes and fibroblasts on FNsyn. The loss of FN synergy site led to normal re-epithelialization caused by two opposing migratory defects of activated keratinocytes and, in the dermis, induced reduced fibrotic responses, with lower contents of myofibroblasts and FN deposition and diminished TGF-beta 1-mediated cell signalling. We demonstrate that weakened alpha 5 beta 1-mediated traction forces on FNsyn cause reduced TGF-beta 1 release from its latent complex.