Mechanisms of Tissue Repair

Damage and injury are a part of life. To survive, every animal must be able to repair tissue damage to restore function and keep out pathogens. Repair requires coordinated cell migration and proliferation, as well as rebuilding extracellular matrix. As in other animals, tissue repair and wound healing are essential in humans, and there is a clinical need for therapies that promote repair to treat non-healing wounds and injuries. However, tissue repair must be regulated: tumors are wounds that do not heal, with cancer cells inappro- priately activating wound-healing programs of migration and proliferation. Moreover, too much deposition of ECM during repair causes fibrosis and scarring, limiting function. Thus, understanding the regulation of repair may have broad clinical applications. My lab investigates repair mechanisms of two common tissue structures that are highly conserved across the animal kingdom: epithelia, the basic cellular building block of animal organs; and basement membrane, the most ancient type of extracellular matrix that underlies epithelia and surrounds muscles, nerves, and organs. We use a Drosophila in-vivo model system for its extraordinary genetic tractability, and we collaborate with physical scientists to address important gaps in understanding these repair processes. For epithelial repair, we collaborate with physicists on high temporal-resolution live-imaging of events happening within milliseconds to seconds after wounding to understand how they lead to later repair behaviors of cells. Although trauma wounds are a chaotic mix of many types of cellular damage, our previous work found that laser damage is in a patterned gradient, enabling us to discover that plasma membrane damage and cell rupture each initiate different but simultaneous signaling pathways. We are addressing how those signals result in cell behaviors that promote wound stabilization and repair. With respect to basement membrane repair, virtually nothing is known about how damage is detected and repaired. We previously developed an assay to analyze matrix damage and scar-free repair using the adult Drosophila gut. Collaborating with a biomedical engineer, we have determined that the surrounding cells detect damage by sensing basement membrane stiffness. We are addressing how that information is conveyed to the cells and how they use it to promote repair. We will address these questions using rigorous genetic approaches combined with the quantitative insight of our physical sciences collaborators. Our results will provide a foundation for understanding the regulation of tissue repair in clinical settings.