Grant: Operating Grant

After skin injury our body rapidly repairs the damage, often leaving behind a stiff scar. Scarring is a clinical burden because skin is losing vital functions. After burns or trauma, scarring makes the skin so inflexible that it can impede the function of muscles, limbs and digits. Worse, uncontrolled wound healing accumulates fibrous tissue. This condition, called fibrosis, is fatal in skin systemic sclerosis and in lung, heart, liver, and kidney fibrosis. To date, no therapy is effective to treat fibrosis. Fibroblasts promote wound healing and fibrosis by secreting fibrous collagen and the growth factor TGFb1. As fibroblasts crawl they pull on the initially soft fibre matrix and make it stiffer. At one point, the matrix is too stiff to be reorganized but still too weak to stabilize the skin. Like cellular Popeyes fibroblasts then turn into powerful contractile 'myofibroblasts'. To make this switch the cells need to get at their 'spinach' - the TGFb1 sitting in the matrix. Using innovative soft culture substrates, we have discovered that cells unlock TGFb1 via a purely mechanical process. In a sufficiently rigid matrix, cell pulling allows the TGFb1 to pop out, like candy from a wrapper. With TGFb1 available, fibroblasts express the muscle proteins needed to contract. The stronger pulling liberates yet more TGFb1 that stimulates other cells to become contractile - a vicious loop is closed. We will use our understanding of mechanical fibroblast activation to fight fibrosis. We can intercept mechanical TGF-beta activation by interfering with integrins, the proteins that cells use to grab on the inactive TGFb1. To identify these yet unknown integrins, we will turn selected integrins on and off, using molecular biology and pharmacological drugs. Effective drugs will be tested in animal models of wound healing and fibrosis. It is our ultimate aim to block TGFb1 activating integrins as a novel clinical strategy to treat fibrosis and to achieve scarless healing.