Skin equivalent tensional force alters keloid fibroblast behavior and phenotype

Skin tension may influence keloid scar behavior, development, and spreading, e. g., butterfly-shaped keloid disease in the sternum. Here, we developed a three-dimensional (3D) in vitro model to mimic in vivo tension and evaluate keloid fibroblast (KF) behavior and extracellular matrix synthesis under tension. In vivo skin tension measured in volunteers (n = 4) using 3D image photogrammetry enabled prediction of actual force (35 mN). A novel cell force monitor applied tension in a fibroblast-populated 3D collagen lattice replicating the in vivo force. The effect of tension on keloid (n = 10) fibroblast (KF) and normal skin (n = 10) fibroblasts (NF) at set time points (6, 12, and 24 hours) was measured in Hsp27, PAI-2, and alpha 2 beta 1 integrin, tension-related genes demonstrating significant (p < 0.05) time-dependent regulation of these genes in NF vs. KF with and without tension. KF showed higher (p < 0.05) proliferation post-tension. Knockdown of all three genes in 24 and 48 hours with and without tension showed significant down-regulation in NF vs. KF. Additionally, we show significant (p < 0.05) modification of the expression of extracellular matrix-related genes post-tension following down-regulation of Hsp27, PAI-2, or alpha 2 beta 1 integrin. Finally, we demonstrate significant alteration in NF compared with KF morphology following knockdown. In conclusion, this study shows induction of tension-related genes expression following mechano-regulation in KFs, with potential relevance to its development and therapy.