A dichotomy exists wherein reticular dermal fibroblasts may express Engrailed-1 (En1) and assume either En1-negative fibroblast (ENF) or En1-positive fibroblast (EPF) lineages. As outlined in Parry and Allison’s review on wound healing, after injury, dermal fibroblasts may activate En1 to become EPFs and contribute to formation of scar tissue. The bifurcation of these dermal fibroblast lineages is regulated by their inherent mechanoresponsiveness. Upon injury, dermal fibroblasts are able to sense mechanical strain via its transduction into a biochemical signal. This strain occurs between a network of cell-ECM interfaces called focal adhesions (FA) (Provenzano and Keely). The mechanotransduction occurring at these interfaces results in the phosphorylation of focal adhesion kinase (FAK), a regulator of FA signaling, resulting in the downstream expression of the Yes-associated protein (YAP). YAP acts as a biomolecular strain status signal, indicating whether fibroblasts are under tension or experiencing mechanical strain, even in unwounded tissue. YAP initiates the signaling cascade which causes ENFs to express En1 and become EPFs, leading to pro-fibrotic tissue development.

By interrupting signaling with the YAP inhibitor, Verteporfin, fibroblasts never receive the signal indicating that tissue is experiencing mechanical strain and, when they are recruited in tissue remodeling, they remain ENFs rather than expressing En1 and becoming pro-fibrotic EPFs. Thus, tissue remodeling occurs with the generation of normally functioning hair follicles, sweat glands, ECM ultrastructure and the mechanical strength and elasticity of unwounded skin.