Date of Award

Fall 1-1-2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy In Applied Biomedical Engineering Degree

Department

Chemical And Biomedical Engineering

First Advisor

Maytin, Edward V.

Second Advisor

Nolan B. Holland, Ph.D.

Third Advisor

Carol de la Motte, Ph.D.

Abstract

Controlled inflammation is crucial for normal wound healing. Our main aim in this study was to investigate the effect of loss of tumor necrosis factor-stimulated gene-6 (TSG-6) in cutaneous wound closure and inflammation. TSG-6 by its enzymatic action modifies the extracellular matrix molecule, hyaluronan (HA), through the transfer of heavy chain (HC) proteins from inter-a-trypsin inhibitor to form HC-HA complexes. Both TSG-6 and HC-HA have been associated with inflammation. Here, we showed that loss of endogenous TSG-6 and HC-HA in TSG-6 null mice results in significantly delayed wound closure and differential neutrophil recruitment compared to wildtype mice. Both of these phenotypes were successfully rescued by reintroduction of TSG-6 into null wounds. We also observed leukocyte recruitment behavior upon chemical injury and propose interesting differences between wildtype and TSG-6 null animals. Further, we showed that levels of the pro-inflammatory cytokine TNFa, and the presence of M1 proinflammatory macrophages, were elevated in TSG-6 null wounds compared to wild type wounds. To facilitate the analysis of wound macrophages, we have described a detailed protocol to isolate single cells from cutaneous wounds. In a nutshell, our study indicates that TSG-6 is required for normal wound closure and plays an important role in regulating inflammation during wound repair.

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