Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry

Tissues lose their integrity upon injury. To rapidly restore mechanical stability, a variety of different cell types is activated to acquire a reparative phenotype - the myofibroblast. Hallmarks of the myofibroblast are secretion of extracellular matrix (ECM), development of adhesion structures with the ECM, and formation of actomyosin contractile stress fibers. Rapid repair comes at the cost of tissue contracture due to the inability of the myofibroblast to regenerate tissue. When contracture and ECM remodeling become progressive and manifest as organ fibrosis, stiff scar tissue obstructs and ultimately destroys organ function. In addition to being a consequence of myofibroblast activities, the mechanical properties of scarred fibrotic organs promote myofibroblast contraction and activation. One essential element in this detrimental feed forward loop is the mechanical activation of the pro-fibrotic growth factor TGF-β1 from stores in the ECM by integrin-mediated cell pulling. We propose that interfering with myofibroblast contraction and integrin-mediated force transmission to latent TGF-β1 and ECM proteins as possible therapeutic strategies to halt fibrosis. More general, the specific mechano-perception and –transmission machinery of myofibroblasts provides multiple targets for possible anti-fibrosis therapies and the most promising approaches will be discussed.