Effect of Mortalin on Scar Formation in Human Dermal Fibroblasts and a Rat Incisional Scar Model

Abstract

Wound healing is a complicated cascading process; disequilibrium among reparative processes leads to the formation of pathologic scars. Herein, we explored the role of mortalin in scar formation and its association with the interleukin-1 alpha receptor using in vitro and in vivo models. To investigate the effects of mortalin, we performed an MTT cell viability assay, qRT-PCR, and Western blot analyses, in addition to immunofluorescence and immunoprecipitation studies using cultured fibroblasts. A rat incisional wound model was used to evaluate the effect of a mortalin-specific shRNA (dE1-RGD/GFP/shMot) Ad vector in scar tissue. In vitro, the mortalin-treated human dermal fibroblast displayed a significant increase in proliferation of type I collagen, alpha-smooth muscle actin, transforming growth factor-beta, phospho-Smad2/3-complex, and NF-kappa B levels. Immunofluorescence staining revealed markedly increased mortalin and interleukin-1 alpha receptor protein in keloid tissue compared to those in normal tissue, suggesting that the association between mortalin and IL-1 alpha receptor was responsible for the fibrogenic effect. In vivo, mortalin-specific shRNA-expressing Ad vectors significantly decreased the scar size and type-I-collagen, alpha-SMA, and phospho-Smad2/3-complex expression in rat incisional scar tissue. Thus, dE1-RGD/GEP/shMot can inhibit the TGF-beta/alpha-SMA axis and NF-kappa B signal pathways in scar formation, and blocking endogenous mortalin could be a potential therapeutic target for keloids.