Biomedical Sciences ETDs

Publication Date

Summer 8-1-2023

Abstract

Acute and chronic injury to the gut has several detrimental consequences. However, dysregulation of secretory lineage cells is a common observation. To model acute gut injury, we use non-fissile uranium bearing dust (UBD), an environmental toxicant prevalent in communities adjacent abandoned uranium mines, majority of which are located in the Southwestern United States. Repeated exposure to environmental toxins and heavy metals has been obscurely linked to intestinal inflammation, increased susceptibility to pathogen-induced diseases, and higher incidences of colorectal cancer. However, there is no molecular evidence that non-fissile uranium can cause damage to the intestinal epithelia. Human colonoids exposed to UBD were used to define the molecular changes that occur in response to this emerging environmental injury to the gut. Here, we characterize the changes in enteroendocrine cells (EEC) in response to UBD exposure, particularly increased differentiation into de novo EEC sub-types. These findings highlight the importance of epithelial differentiation as major colonic responses to heavy metal-induced injury

Decrease in goblet cells and mucus production has been observed during chronic inflammation in the gut. The mechanism that underlie this dysregulation is not well understood. To model chronic gut injury, we used colonoids from Il10-/- mice, a well characterized mouse model of chronic intestinal inflammation. Our data indicates that inflammatory macrophages upregulate notch ligand expression, activates notch signaling via cell-cell interactions, and inhibit secretory lineage differentiation in the colonic epithelium.

For the first time, this study provides molecular evidence that environmental toxicants such as uranium bearing dust can cause damage to the gut by diminishing the proliferative pool of cells thereby compromising the regenerative potential of the epithelium. Acute UBD injury induced expansion of hormone producing enteroendocrine cells suggesting a regenerative function. We identified a potential non-canonical mechanism of enteroendocrine differentiation that is injury dependent and possibly reliant on the WNT-dependent transcription factor PROX1. We confirm previous findings of enteric glucagon production by humans and identified the cellular origin. We elucidated the mechanism by which inflammatory macrophages activate notch signaling and inhibit secretory lineage differentiation during chronic inflammation in the gut. This mechanism serves as potential target for IBD therapies. In summary, secretory lineage cells are central to acute and chronic injury response in the gut. They expand upon acute injury and decrease during chronic injury.

Keywords

Enteroendocrine cells, colonoids, secretory differentiation, inflammatory macrophages, non-fissile uranium dust

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Julie G. In

Second Committee Member

Jennifer M. Gillette

Third Committee Member

Judy L. Cannon

Fourth Committee Member

Eliseo F. Castillo

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