Insights into the Molecular and Epigenetic Mechanisms Involved in Tissue Regeneration and Infections
Abstract
Thousands of patients require esophageal replacement annually. While immune activation is critical for wound-healing processes and tissue regeneration, chronic non-resolving inflammation can cause fibrosis, tissue damage, and disease. Given recent evidence that immune regulation becomes dysfunctional with aging, there is a vital need to better understand the host immune responses involved in tissue regeneration and inflammation. Previous studies identified signaling pathways involved in tissue regeneration with acellular graft implants such as the phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), and hepatocyte growth factor receptor (c-MET) signaling pathways. However, whether and how epigenetic mechanisms influence tissue regeneration has not been studied. A better understanding of the epigenetic mechanisms involved in regeneration and how they are connected to disease can help identify novel therapeutic targets and improve our ability to determine when these biological systems have gone awry.In chapter 2, we discuss a potential novel mechanism for how the loss of DNA methylation during aging could contribute to immune dysfunction through a novel analysis of previously published epigenetic data and a review of the literature. In chapter 3, we characterized DNA methylation dynamics during tissue regeneration and present novel findings that suggest epigenetic mechanisms influence key signaling pathways involved in growth, inhibition of apoptosis, and immune activation in regenerating esophageal epithelial tissues. Our results showed that hypomethylation of CpGs occurs within the promoters of genes associated with immune activation, while hypermethylation of CpGs occurs in the promoters of genes involved in PI3K-Akt activation. Taken together, the findings in chapter 2 and chapter 3 provide insights into how epigenetics changes are important regulators of immune responses and may influence immune dysfunction during aging when cells exhibit a notable loss in regenerative potential. The results of this work can help identify novel opportunities to improve the efficacy of biomedical implants by manipulating epigenetic mechanisms involved in immune activation to promote wound healing and tissue regeneration. Finally, in chapter 4, we discuss findings from a collaborative project that showed the gram-negative bacteria, Pseudomonas aeruginosa, responds to the presence of stimulated neutrophils by activating the fro system, which regulates the expression of antioxidative genes to mitigate the bactericidal effects of HOCl. Our results suggest that fro activation could function as a bacterial defense mechanism against a neutrophil attack mechanism which could promote colonization in human tissues.