Date of Award

Spring 2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Molecular, Cellular, and Developmental Biology

First Advisor

Horsley, Valerie

Abstract

Mammalian skin is complex, heterogeneous, and essential for survival. It is the primary barrier that protects us from physical, microbial, and chemical hazards, and must therefore be highly regenerative. When skin is wounded, healing occurs through a series of temporally-overlapping and tightly regulated stages of inflammation, proliferation, and remodeling. Angiogenesis, the growth of new blood vessels from pre-existing vessels, occurs during the proliferative phase of repair and is essential for the formation of new, healthy tissue. Blood vessels are a vital source of oxygen, nutrients, and immune cells, and failure of these vessels to regenerate after injury results in chronic, non-healing wounds. Chronic wounds represent a staggering portion of global healthcare costs, and these costs will continue to rise as the population grows older and more diabetic. It is therefore imperative that we thoroughly characterize the signals that govern angiogenesis in order to inform the development of new, effective therapies to rescue skin revascularization and healing.The two major goals of this work are (I) to characterize the angiogenic niche in healing skin, and (II) to determine if Langerhans cells (LCs), a type of phagocytic, skin-resident immune cell, play a role in skin revascularization and repair. We provide a map of an early angiogenic niche by analyzing single-cell RNA sequencing of mouse skin wound healing. Within skin wounds, endothelial cells receive several, specialized signals from multiple cell types, including well- described interactions with fibroblasts, macrophages, and keratinocytes. These data also implicate LCs in driving angiogenesis during skin repair. Using lineage- driven reporters, three-dimensional (3D) confocal microscopy, and mouse genetics, we show that LCs are spatially situated at the leading vascular edge of skin wounds and are necessary for angiogenesis during wound repair. These data provide future avenues for the control of angiogenesis to treat disease and chronic wounds, and extend the function of LCs beyond their canonical role in antigen presentation and T-cell immunity.

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