Identification and Characterization of Gastric Stem Cells in Drosophila

Date of Award

Winter 12-15-2013

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Developmental, Regenerative, & Stem Cell Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Proper organ function and tissue maintenance is crucial for the longevity of adult organisms. Adult stem cells function as a cellular reservoir in renewing tissues to replace cells that are lost from damage or injury. Stem cells have the unique ability to self-renew and replenish differentiated cells lost throughout an organism's lifetime, thus preserving tissue function. The mammalian gastrointestinal (GI) tract is one of the most rapidly renewing tissues and is supported by distinct stem cell populations. Recent advances in the murine system have molecularly identified stem cell populations in the mammalian small intestine, however a population of gastric stem cells in the stomach has yet to be identified at single-cell resolution.

Similar to the mammalian GI tract, the Drosophila midgut has a segmental organization, displaying physiological compartmentalization and region-specific epithelia. The adult Drosophila copper cell region or "stomach" is a highly acidic compartment of the midgut with pH < 3. In this region, a specialized group of acid-secreting cells, analogous to mammalian gastric parietal cells, have been identified by a unique ultrastructure and by copper-metallothionein fluorescence. However, the homeostatic mechanism maintaining the acid-secreting copper cells of the adult midgut had not been examined.

In this thesis, we combine cell lineage tracing and genetic analysis to investigate the mechanism by which the gastric epithelium is maintained in Drosophila. Our studies show that a molecularly identifiable population of multipotent, self-renewing gastric stem cells (GSSCs) produces the acid-secreting copper cells, interstitial cells, and enteroendocrine cells of the adult copper cell region. Our assays demonstrate that GSSCs are largely quiescent but can be induced to rapidly regenerate the gastric epithelium in response to environmental challenge. Finally, genetic analysis demonstrates that the conserved mitogenic EGF signaling pathway is a limiting factor controlling GSSC proliferation. The lowest level of EGF activity along the Drosophila GI tract is found in the copper cell region under baseline conditions when GSSCs are largely quiescent. However, acute injury by enteric pathogens leads to an increase in EGF ligand expression, which is associated with the rapid expansion of the GSSC lineage. EGF pathway activation, specifically in the progenitor cell population, is sufficient to induce proliferation in the normally quiescent stem cell population. In addition, EGF signaling is required for expansion of the gastric lineage and necessary for injury induced proliferation. Characterization of the gastric stem cell model in Drosophila, with striking similarities to mammals may be relevant to advance our understanding of both homeostatic and pathogenic processes in human.

Language

English (en)

Chair and Committee

Craig A Micchelli

Committee Members

David C Beebe, Aaron DiAntonio, Stephen L Johnson, Jason C Mills, James B Skeath

Comments

Permanent URL: https://doi.org/10.7936/K72N5060

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