Phenotypic differences between dermal fibroblasts from different body sites determine their responses to tension and TGFβ1

BACKGROUND Wounds in the nonglabrous skin of keloid-prone individuals tend to cause large disordered accumulations of collagen which extend beyond the original margins of the wound. In addition to abnormalities in keloid fibroblasts, comparison of dermal fibroblasts derived from nonwounded glabrous or nonglabrous skin revealed differences that may account for the observed location of keloids. METHODS Fibroblast apoptosis and the cellular content of alpha-smooth-muscle actin, TGFbeta1 receptorII and ED-A fibronectin were estimated by FACS analysis. The effects of TGFbeta1 and serum were examined. RESULTS In monolayer cultures non-glabrous fibroblasts were slower growing, had higher granularity and accumulated more alpha-smooth-muscle actin than fibroblasts from glabrous tissues. Keloid fibroblasts had the highest level of alpha-smooth-muscle actin in parallel with their expression level of ED-A fibronectin. TGFbeta1 positively regulated alpha-smooth-muscle actin expression in all fibroblast cultures, although its effects on apoptosis in fibroblasts from glabrous and non-glabrous tissues were found to differ. The presence of collagen I in the ECM resulted in reduction of alpha-smooth-muscle actin. A considerable percentage of the apoptotic fibroblasts in attached gels were alpha-smooth-muscle actin positive. The extent of apoptosis correlated positively with increased cell and matrix relaxation. TGFbeta1 was unable to overcome this apoptotic effect of matrix relaxation. CONCLUSION The presence of myofibroblasts and the apoptosis level can be regulated by both TGFbeta1 and by the extracellular matrix. However, reduction of tension in the matrix is the critical determinant. This predicts that the tension in the wound bed determines the type of scar at different body sites.