ORCID
https://orcid.org/0000-0002-6924-2433
Date of Award
8-14-2023
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
The stomach contains gastric epithelial cells, including acid-pumping parietal cells (PCs), that are constantly renewed throughout life from a multipotent stem cell to maintain a balance between producing and protecting from the acid and enzymes needed to kill pathogens and initiate digestion. Despite this dynamic renewal, disorders of the gastric epithelium occur and are one of the most common etiologies of human diseases ranging from simple heartburn to reflux, peptic ulcers and gastric cancer. PCs are characterized by elaborate plasma membrane foldings and vesicles that house their proton pumps and an abundance of mitochondria needed to power secretion of that acid. Surprisingly, little is known about the mechanisms underlying how PCs differentiate from the gastric epithelial stem cell to lay down this complex cellular architecture. Indeed, little is known about the transcriptional regulation of differentiation of any gastric epithelial cell types. Understanding the pathways that guide PC regeneration could yield targets to treat ailments characterized by PC dysregulation or loss and provide insight into mechanisms for cells fate decisions for multiple gastric epithelial lineages. Using new and cutting-edge tools in the gastric field including new genetic tools and sequencing techniques, my thesis work has identified and interrogated a new pathway and a candidate transcriptional regulator of PC specification and maturation: AMPK and ERRγ. After observing that AMPK, an intracellular energy sensor, is enriched in the PC population, mouse models were used to demonstrate that at homeostasis and after gastric injury, parietal cell-specific deletion of AMPK and its target PGC1α increased progenitor proliferation and decreased PC census and maturation. Conversely, when AMPK was pharmacologically activated with metformin, progenitor proliferation decreased while parietal regeneration increased. KLF4 was identified as a progenitor-cell-specific target of AMPK. PGC1α was confirmed as a target in mature PCs. Next, using a new transgenic model that allows for PC-specific ablation, I was able to identify Estrogen-related receptor gamma (ERRγ) as a candidate marker for early and mature PCs. Extensive histologic and transcriptional analysis of PCs throughout regeneration revealed a population of PC progenitors. Such pre-PCs were a transcriptionally distinct population, characterized by co-expression of progenitor, proliferation, mature PC markers, and ERRγ. Furthermore, PC differentiation was entirely dependent on ERRγ, as its ablation from either embryonic or PC progenitors resulted in total absence of mature PCs. For the first time, this work defines the temporal ultrastructural and molecular stages of PC differentiation from stem cells. Additionally, I identify the first transcriptional regulators of PC differentiation showing that PC fate specification requires metabolically-influenced pathway centering on AMPK, ERRγ, and PGC1α. ERRγ can be used as an efficient biomarker for identifying PC progenitors in human disease. Both AMPK and ERRγ can be targeted by existing drugs to promote PC regeneration and reverse or prevent ailments characterized by PC loss. Moreover this work has elucidated pathways essential for gastric stem cell differentiation to maintain a healthy gastric epithelium.
Language
English (en)
Chair and Committee
Jason Mills
Committee Members
Lilianna Solnica-Krezel
Recommended Citation
Adkins-Threats, Mahliyah Lenore, "Investigation of Metabolic and Molecular Pathways that Promote Gastric Parietal Cell Regeneration" (2023). Arts & Sciences Electronic Theses and Dissertations. 3113.
https://openscholarship.wustl.edu/art_sci_etds/3113