A TGF-beta1-dependent autocrine loop regulates the structure of focal adhesions in hypertrophic scar fibroblasts.
Following injury, fibroblasts migrate into wounds and differentiate into alpha 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 alpha SMCA-rich stress fibers. Following severe traumatic or thermal injury to the dermis, hypertrophic scars (HTSs) often develop and these scar fibroblasts (HTSFs) express alpha 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 beta1 (TGF-beta1). 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-beta1 receptor mimetic. Human foreskin fibroblasts transduced with a retrovirus encoding active TGF-beta1 elaborate large focal adhesions, whereas fibroblasts overexpressing normal, latent TGF-beta1 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-beta1; these adhesions likely mediate both tighter adhesion to wound matrix and the exuberant wound contraction observed in pathogenic scars.
Dabiri
Ganary
G
Center for Cell Biology and Cancer Research, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA.
Campaner
Anelisa
A
Morgan
Jeffrey R
JR
Van De Water
Livingston
L
D000328:Adult; D002478:Cells, Cultured; D017439:Cicatrix, Hypertrophic / Q000503:physiopathology*; D017077:Culture Media, Conditioned; D005347:Fibroblasts / Q000502:physiology; D005353:Fibronectins / Q000378:metabolism; D022001:Focal Adhesions / Q000502:physiology*; D006801:Humans; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D012190:Retroviridae / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*; D053773:Transforming Growth Factor beta1
D017077:Culture Media, Conditioned; D005353:Fibronectins; D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1