Wound Healing and Fibrosis
Our lab is studying the mechanisms that regulate wound healing. We are using the cornea as a model system because corneal transparency is critical for clear, unobstructed vision, making it an important tissue in which to study fibrotic scarring. The cornea refracts light as it enters the eye so that a properly focused image reaches the retina. When a cornea is wounded by surgery or injury, the wound heals unpredictably, either regeneratively (without scarring) or fibrotically (with scarring). Our goal is to understand the mechanisms that promote regenerative wound healing over fibrotic healing and to apply these finding not only to the cornea, but to other models of fibrotic disease.
Corneal wound healing begins when cells (fibroblasts) migrate into the wound site producing repair matrix as they migrate. Induced by the Growth Factor, TGFβ, fibroblasts differentiate into contractile cells (myofibroblasts) that adhere to the surrounding matrix and pull the matrix fibers together, closing the wound. In a regeneratively healed wound, myofibroblasts disappear by apoptosis, whereas the persistence of myofibroblasts results in the overproduction of extracellular matrix, excessive contraction, and an autocrine loop of TGFβ activity that leads to scarring. Regulation of both fibroblast migration and myofibroblast differentiation are critical for promoting regenerative repair.
To better understand the molecular basis for cell migration and cell differentiation, we have focused on the role of the urokinase (uPA) pathway during wound healing. uPA is an extracellular serine protease that stimulates both a protease cascade at the cell-matrix interface and an intracellular signaling cascade resulting in cytoskeletal reorganization and cell migration. We have found dramatic differences in the uPA pathway between fibroblasts and myofibroblasts. Our work has demonstrated that this pathway is an important regulator of myofibroblast differentiation, integrin function, and TGFβ signaling. We continue to investigate the basic mechanisms that lead to fibrosis and we are working on generating therapeutics targeted at the uPA pathway to control fibrotic healing.
Research Topics Cell adhesion and extracellular matrix Cell migration Cell differentiation Proteases