Doctor of Philosophy
Anatomy and Cell Biology
Hamilton, Douglas W.
Flynn, Lauren E.
Chronic wounds represent a major health problem primarily affecting patients with underlying pathologies including diabetes and vasculopathy. These wounds are characterized by an impaired transition from the inflammatory to the proliferative phase of healing. In this thesis, the complex relationship between cells and their microenvironment was explored in the context of wound healing by investigating how intrinsic differences in fibroblasts affect their response to external stimuli, and how extracellular matrix (ECM) proteins modify cellular responses during acute wound repair. First, it was hypothesized that different subpopulations of fibroblasts could be identified in cutaneous tissue based on divergent embryonic expression patterns of the transcription factor Foxd1, and that these subpopulations would play varying roles during wound repair. Next, it was hypothesized that wound repair could be modulated in animal models by altering components of the ECM. To explore cell-intrinsic differences in the skin, a lineage tracing approach was applied to observe a population of cells derived from embryonic Foxd1-expressing progenitors during embryonic development and into adulthood. These cells contributed to a subpopulation of fibroblasts in adult dorsal skin that were enriched with transcripts for matrix modifying genes during homeostasis and following wounding relative to fibroblasts not of this origin. Next, Galectin-3, a multifunctional matricellular protein with pro-angiogenic, pro-fibrotic, and immunomodulatory properties in models outside of skin, was investigated to assess the role of this cell-extrinsic factor during cutaneous healing in mice and in human chronic wounds. Using a genetic deletion strategy, it was determined that galectin-3 was iii dispensable during acute repair in mice. Finally, pilot studies were performed to investigate an acute wound model in juvenile pigs for assessing foam biomaterials derived from the ECM as a strategy to modulate wound healing by targeting the cellular microenvironment. While modifying the matrix composition of the biomaterials did not alter healing in this model, the findings support that further exploration into relevant models of impaired healing is warranted. Overall, the studies in this thesis have helped to elucidate complex interactions between cells and their environment during wound repair, providing relevant information for the design of future therapeutics for chronic wounds.
Walker, John, "Cell Recruitment and Differentiation in Wound Repair" (2019). Electronic Thesis and Dissertation Repository. 6063.
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Available for download on Tuesday, December 01, 2020