Mechanisms regulating inflammatory fibroblasts in wound healing

Project Summary Wound healing is a central aspect of human health that is a coordinated process involving multiple cell populations. Interactions between the microenvironment, recruited cell populations, and tissue-resident cell populations, in particular stromal and immune cell populations, is critical for successful wound healing. Dysregulated wound healing contributes to fibrosis/fibrotic disorders, which have been attributed to approximately 45% of deaths in the developed world. Typically in wound healing, inflammation is spatially and temporally controlled and subsequently the tissue is remodeled by activated fibroblasts and myofibroblasts, whose presence and survival is also tightly regulated by other cells and environmental cues. In dysfunctional wound healing, chronic immune cell infiltration and proinflammatory cytokines overlap with the emergence of fibroblasts poised to promote fibrosis. The fate and function of fibroblasts has been identified to be a determining factor in wound healing. The inflammatory component of wound healing has been well characterized and even more so the myofibroblast and ECM components. However, there is a dearth of studies investigating how immune-stromal crosstalk contributes to wound healing, as well as whether fibroblasts contribute to perpetuate chronic inflammation. The regulation of inflammation has a critical effect on downstream fibroblast phenotypes, which also contributes to whether wound healing occurs. Recent work has characterized a specific fibroblast subpopulation, inflammatory fibroblasts, that contributes to inflammatory signaling. Yet what is unknown is their role in wound healing and whether the resolution and regulation of inflammatory fibroblasts is an important aspect of wound healing. Understanding the role and regulation of inflammatory fibroblasts in wound healing is a central objective of this application. Our lab is focused on addressing these challenges by integrating single cell approaches, biomaterials, and in vivo models of wound healing and tissue repair that altogether offer an outstanding opportunity to understand mechanisms regulating inflammatory fibroblasts and their contribution in either facilitating or hindering wound healing. We propose the following projects towards addressing these challenges: Project 1) Determinign the contribution of inflammatory fibroblasts during wound healing; Project 2) Identifying pathways that regulate inflammatory fibroblasts in wound healing; Project 3) Identifying mechanisms of inflammatory fibroblast-mediated changes to the ECM. Addressing these challenges will provide fundamental new insights in fibroblast biology, inflammation, and identifying new avenues for therapeutic approaches.