Dissecting the contributions of Langerhans cell to cutaneous wound healing

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PROJECT SUMMARY Wound healing is a critically important field of healthcare, yet current medical technologies fail to address the needs of 6.5 million patients who suffer from chronic injuries in the United States alone. Each year, non- healing wounds inflict a $37 billion burden on the U.S. healthcare system. As the country’s population continues to age and become increasingly diabetic, these numbers are projected to consistently rise. The development of therapeutic strategies to mitigate the toll of non-healing wounds relies on basic understanding of the mechanisms that regulate skin repair. The goal of this work is to improve this understanding by identifying signaling events that drive successful skin regeneration, and specific cell types responsible for propagating those signals. We recently revealed that Langerhans cells (LCs), a subset of skin-resident immune cells, are imperative to successful wound healing, particularly for the formation of new blood vessels. Little is known, however, about the specific function of LCs during cutaneous repair. Using genetically engineered mouse models in which LCs can be specifically targeted for cell death or deletion of specific genes, we propose to investigate the timing and molecular mechanisms through which LCs mediate wound healing. We hypothesize that in response to skin injury, LCs secrete Vascular Endothelial Growth Factor A (VEGFa) into the cutaneous macroenvironment to promote angiogenesis and dermal repair. This hypothesis is based on: 1) our data that in the absence of LCs, reparative processes—such as revascularization—are completely abrogated, and 2) our preliminary findings that LCs express the gene for VEGFa at multiple time points during wound healing. In this project, we will define the specific cellular processes that LCs direct during the proliferative phase of wound healing, as well as the signaling molecule required to perform one of these functions: revascularization.