Grant: Project Grant

Different cells are activated to rapidly repair injured tissues. These cells are called myofibroblasts because they secrete fibrous collagen matrix ("fibro") that is contracted ("myo") into mechanically stabilizing scar tissue. Myofibroblasts deregulation leads to excessive scarring - a condition called fibrosis. Fibrosis contributes to the destruction of vital organs such as heart, liver, kidney and lung and accounts for ~33% of deaths globally and ~45% in industrialized nations. Myofibroblast activation, proliferation, matrix processing, and survival are controlled by growth factors secreted by inflammatory cells - macrophages. In fact, one driving element in fibrosis is the chronic co-existence of macrophages and myofibroblasts. We have recently identified specific intercellular junctions that maintain spatial proximity of macrophages and myofibroblasts, which is needed to ensure that special pro-fibrotic growth factors are handed over from one cell to the other. However, the guidance cues initially attracting migratory macrophages to contracting myofibroblasts over millimeter ranges in collagen matrix-rich tissues are unknown. Based on exciting preliminary findings we propose a new mechanism where the pulling activity of contracting myofibroblasts generates far-reaching physical cues in the matrix that mechanically attract macrophages. Analogous to a struggling (but not a dead) fly in a spider web, myofibroblasts create dynamic disturbances in collagen nets that attract macrophages (the metaphorical spider). Using a variety of high-end biomechanical, bioengineering and genetic approaches, we will decipher the molecular mechanisms and proteins that allow macrophages to detect and follow these mechanical signals. Specific inhibition of these yet unidentified mechanisms is proposed as a potential new therapeutic strategy to counteract fibrosis.