Biochemical and biomechanical regulation of the myofibroblast phenotype:focus on Hippo and TGFβ signaling

Abstract

The extracellular matrix (ECM) is a dynamic collection of proteins and carbohydrates, which are constantly synthesized, modified, and degraded by cells. In chronic disorders such as fibrosis, ECM synthesis and degradation are out of balance, and myofibroblasts alter the composition and cross-linking of the matrix. The replacement of normal functional ECM with collagenous scar tissue causes distortion of tissue architecture by contraction of the connective tissue. Understanding how myofibroblasts transduce biomechanical and biochemical cues to modulate the regulation of gene transcription is of paramount importance for the development of anti-fibrotic therapeutics. The aim of this thesis was to elucidate how biomechanical and biochemical cues regulate the myofibroblast phenotype. To this end, we focused on three main areas of research. First, we uncovered an important role for YAP signaling in myofibroblasts and the fibroproliferative disorder Dupuytren disease. We provide novel insights in how YAP regulates the myofibroblast phenotype, by interacting with Smad transcription factors. Second, we found that the spectrin cytoskeleton does not seem to be involved in fibroblast mechanosensing and the formation of a myofibroblast phenotype. Finally, we show how vitamin C acts as important co-factor for functioning of myofibroblasts. In conclusion, our findings do not only provide a better understanding of the myofibroblast phenotype and fibrosis, but also provide support for changes in general laboratory practice and tools for the possible treatment of fibrosis