FAK-dependent regulation of myofibroblast differentiation

Fibroblasts and myofibroblasts both participate in wound healing. Transforming growth factor beta (TGF beta) induces fibroblasts to differentiate into myofibroblasts, whereas fibroblast growth factor and heparin (FGF/ h) induce myofibroblasts to de-differentiate into fibroblasts. TGF beta induces expression of smooth muscle alpha actin (SM alpha A) and incorporation into in stress fibers, a phenotype of differentiated myofibroblasts. Additionally, TGF beta induces the expression of fibronectin and fibronectin integrins. Fibronectin-generated signals contribute to the TGF beta-mediated myofibroblast differentiation. Because fibronectin signals are transmitted through focal adhesion kinase (FAK), it was predicted that FAK would be essential to TGF beta-mediated myofibroblast differentiation. To determine whether the FAK signaling pathway is required for myofibroblast differentiation, we used two approaches to decrease FAK in mouse embryo fibroblasts (MEFs): 1) FAK+/+ MEFs, in which FAK protein expression was greatly decreased by short hairpin RNA (shRNA), and 2) FAK-/-MEFs, which lack FAK. In both cases, the majority of cells were myofibroblasts, expressing SM alpha A in stress fibers even after treatment with FGF/ h. Furthermore, both the surface expression of FGFRs and FGF signaling were greatly reduced in FAK-/-MEFs. We conclude that FAK does not contribute to TGF beta-dependent myofibroblast differentiation. Instead, FAK was necessary for FGF/ h signaling in down-regulating expression of SM alpha A, which is synonymous with myofibroblast differentiation. FAK activation could contribute to regulating myofibroblast differentiation, thereby ameliorating fibrosis.