Activin-mediated alterations of the fibroblast transcriptome and matrisome control the biomechanical properties of skin wound

Abstract

Matrix deposition is essential for wound repair, but when excessive, leads to hypertrophic scars and fibrosis. Here, we determined the interrelationship between the fibroblast transcriptome, the matrisome and the biomechanical properties of healing wounds. Using genetically-modified mice we show how a single diffusible factor, activin A, affects the healing process across scales. Bioinformatics analysis of wound fibroblast transcriptome data combined with biochemical and histopathological analyses of wounds and functional in vitro studies revealed that activin promotes pro-fibrotic gene expression signatures and processes, including glycoprotein and proteoglycan biosynthesis, collagen deposition, and altered collagen cross-linking. As a consequence, activin strongly reduces the wound and scar deformability, as revealed by a novel, non-invasive in vivo method for biomechanical analysis. These results provide mechanistic insight into the roles of activin in wound repair and fibrosis and identify the functional consequences of alterations in the wound matrisome at the biomechanical level.