A TGF-β1-Dependent Autocrine Loop Regulates the Structure of Focal Adhesions in Hypertrophic Scar Fibroblasts

Following injury, fibroblasts migrate into wounds and differentiate into α smooth muscle cell actin (SMCA)-positive cells, termed myofibroblasts, that assemble and remodel the scar. Cultured myofibroblasts assemble larger focal adhesions than do normal dermal fibroblasts and these focal adhesions attach to α SMCA-rich stress fibers. Following severe traumatic or thermal injury to the dermis, hypertrophic scars (HTSs) often develop and these scar fibroblasts (HTSFs) express α SMCA persistently. We now report that HTSFs stably display large focal adhesions as a consequence of both the autocrine production and activation of transforming growth factor β1 (TGF-β1). We also observe that myofibroblasts elaborating larger focal adhesions adhere more tightly to fibronectin. Conditioned medium from HTSFs induces focal adhesion growth in normal fibroblasts and this is blocked by pre-incubation with a soluble TGF-β1 receptor mimetic. Human foreskin fibroblasts transduced with a retrovirus encoding active TGF-β1 elaborate large focal adhesions, whereas fibroblasts overexpressing normal, latent TGF-β1 do not. We conclude that the large focal adhesions found in pathogenic myofibroblasts arise through an autocrine loop involving the production and activation of TGF-β1; these adhesions likely mediate both tighter adhesion to wound matrix and the exuberant wound contraction observed in pathogenic scars.