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Thesis Format

Integrated Article

Degree

Master of Science

Program

Pathology and Laboratory Medicine

Supervisor

Asfaha, Samuel

Abstract

Mouse models of colitis are used ubiquitously to study inflammatory bowel disease (IBD); however, we lack a thorough understanding of how these models work and which model recapitulates IBD most faithfully. This study profiled 8,777 single colonic immune cells to compare and better characterize the immune cell responses of DSS and oxazolone-induced colitis. Our results show differential abundance of neutrophil subtypes between the models, as well as presence of a putative colitis-associated colorectal cancer-initiating population of Ly6cHi monocytes unique to DSS. Comparisons between the models and a single-cell dataset of ulcerative colitis (UC) suggest DSS more closely resembles the immune response in patients. Moreover, Ly6cHi monocytes elevated in DSS were found to closely resemble inflammatory macrophages and monocytes in UC. Altogether, this study provides a single-cell characterization of the immune responses of these models and demonstrates DSS is more faithful to the immune response seen in UC patients.

Summary for Lay Audience

Inflammatory bowel disease (IBD) is comprised of ulcerative colitis (UC) and Crohn’s disease (CD). Both are incurable intestinal disorders characterized by lifelong episodes of intestinal inflammation and remission. For over 200,000 Canadians, IBD significantly impacts quality of life and represents a substantial burden on the Canadian health care system and society.

For the last 30 years, mouse models of colitis have served as important avenues for pinpointing mechanisms that contribute to human disease and to testing treatment candidates. Although mouse models of colitis are used ubiquitously to study IBD, we lack a thorough understanding of how these models work and which model recapitulates IBD most faithfully. Furthermore, it has been recently shown that these models differ in their ability to predispose mice to a complication of IBD known as colitis-associated colorectal cancer (CAC). To address these shortcomings, this study conducted single-cell RNA sequencing (scRNA-seq) on the commonly used DSS and oxazolone-induced mouse models of colitis. This was done to compare and better characterize their immune response and how it relates to patients. Using scRNA-seq the expression of each gene can be tracked in each individual cell, thereby enabling cell-to-cell comparisons between the mouse models.

Our results show differential abundance of neutrophil subtypes between the models. Immature and mature neutrophils were present in DSS, whereas an aged population of Ly6gLo neutrophils was identified in oxazolone. Additionally, a putative CAC-initiating population of immune cells known as Ly6cHi monocytes was elevated in DSS. Comparisons between the models and a single-cell dataset of UC suggest DSS more closely resembles the immune response in patients. Moreover, Ly6cHi monocytes were found to closely resemble inflammatory macrophages and monocytes in UC. Altogether, this study provides a single-cell characterization of the immune responses of these models and demonstrates DSS is more faithful to the immune response seen in UC patients.

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

Available for download on Sunday, September 01, 2024

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