The Macrophage-myofibroblast connection in fIbrosis

Tissues lose integrity upon injury. To rapidly restore mechanical stability, a variety of different cell types are 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. Pivotal for the formation of myofibroblasts are mechanical stimuli arising during tissue repair and chronic persistence of inflammatory cells. High stress, partly being a consequence of myofibroblast activities, amplifies scarring whereas absence of stress suppresses myofibroblast activities. I will give an overview on our current projects that address how mechanical factors orchestrate the development of myofibroblasts: (1) by mechano-sensing of tissue stiffness, (2) controlling the bioavailability of pro-fibrotic TGF-β1, and (3) mediating communication between myofibroblasts and macrophages. By understanding and manipulating myofibroblast and macrophage mechanoperception we will be able to devise better therapies to reduce scarring and support normal wound healing.