Wound healing and inflammation studies in genetically tractable organisms

Tissue repair in embryos is rapid, efficient and perfect and does not leave a scar, an ability that is lost as development proceeds. There are two very clear differences between embryonic and adult tissues that may explain this phenomenon and these differences guide our experiments. First, embryonic tissues undergo morphogenesis - they fold and bend and migrate in order to build the overall body plan, and to shape various organs. Adult tissues by contrast are relatively dormant. Our thesis is that wound healing recapitulates morphogenesis and so tissues that are actively pursuing morphogenesis are more efficient at re-activating this “repair machinery”. We study parallels between wound healing and several morphogenetic episodes, noteably dorsal closure in Drosophila and eyelid fusion in mice, in order to reveal fundamental cell and molecular mechanisms that are common to both processes and might guide in design of therapeutic tools to make wounds heal faster and better. Second, any tissue damage in the adult, triggers a robust inflammatory response but in embryos this response is much reduced or absent. In PU.1 knockout mice which genetically lack all leukocytes and are unable to raise an inflammatory response, we can show that inflammation, per se, is not essential for healing and we can distinguish the molecular consequences of the wound inflammatory response by microarray subtraction of the mRNAs expressed at the wound site in wild-type versus inflammation-minus, PU.1 KO mice. Complementary studies of inflammation in Drosophila embryos and zebrafish larvae allow us to live image the wound inflammatory response and provide opportunities to dissect the genetics of inflammatory cell recruitment to wounds, which in turn may allow us to identify gene targets for therapeutically modulating the recruitment of inflammatory cells and thus improving adult healing.