Date of Award
Spring 2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Molecular, Cellular, and Developmental Biology
First Advisor
Horsley, Valerie
Abstract
The skin is an essential barrier against the outside world, and must withstand constant exposure to damage from the environment. When this barrier is broken, it must be repaired quickly and effectively in order to prevent infection and restore function. The skin’s ability to heal wounds is vital for human health, and insufficient wound treatment is a major clinical problem, contributing to decreased quality of life and increased healthcare costs for many patients due to chronic or non-healing wounds. The complex process of wound healing involves the coordination of many cell types and signals, which were here investigated using single-cell RNA sequencing to provide a map of the cellular dynamics during early inflammation in mouse skin wounds. This dataset showed that cell death, particularly programmed cell death (apoptosis), is widespread between 24 and 48 hours after injury, resulting in changed cell populations over time. Apoptosis and clearance of apoptotic cells via efferocytosis are evolutionarily conserved processes that drive tissue repair. However, the mechanisms by which recognition and clearance of apoptotic cells regulate repair are not fully understood. In skin wounds, it was found that apoptotic pathways and efferocytosis receptors were elevated in fibroblasts and immune cells during inflammation. Despite the prevalence of cell death, dead cells were not widely observed in skin wounds, due to the efficient clearance of these dead cells by efferocytosis. One receptor important for this process, Axl, was highly upregulated after injury and expressed by both dendritic cells and fibroblasts. Axl expression was upregulated by TLR3 signaling, but could also be initiated by TLR3-independent mechanisms, indicating multiple redundant pathways for Axl function. Finally, antibody inhibition experiments in vivo in mice revealed that Axl signaling is necessary for effective wound repair, but is dispensable for efferocytosis. In particular, Axl was required for proper revascularization and fibroblast repopulation in the wound bed during the proliferative stage of healing. These data highlight the distinct mechanisms by which apoptotic cell detection, particularly via the receptor Axl, coordinates tissue repair, as well as providing potential therapeutic targets for chronic wounds.
Recommended Citation
Justynski, Olivia, "Apoptosis recognition receptors regulate skin tissue repair in mice" (2023). Yale Graduate School of Arts and Sciences Dissertations. 879.
https://elischolar.library.yale.edu/gsas_dissertations/879
