Characterization of interstitial cells and their role as regulators of motility and neural pathways in the esophageal region
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Authors
Ni Bhraonain, Emer
Issue Date
2025
Type
Dissertation
Language
en_US
Keywords
Esophagus , Interstitial Cells , Lower Esophageal Sphincter , Motility , Muscle , Neurons
Alternative Title
Abstract
The esophagus transports ingested contents from the mouth to the stomach where they pass through the high-pressure zone of the gastroesophageal junction (GEJ). Within the GEJ the lower esophageal sphincter (LES) generates tone to increase luminal pressure, meanwhile the distal esophagus generates phasic contractions which may also contribute to high-pressure. During swallowing the GEJ must transiently relax before contracting again to prevent reflux. This entire process of swallowing requires integrated coordination of the activity of smooth muscle cells (SMCs), striated muscle, interstitial cells and nerve fibers. This dissertation investigates the cellular and molecular mechanisms contributing to control of motility in the esophageal region, focusing on the role of intramuscular interstitial cells of Cajal (ICC-IM) and platelet-derived growth factor receptor alpha positive (PDGFRα⁺) cells. Using mouse and non-human primate (Cynomolgus Macaque; monkey) tissue, we demonstrated that the distal esophagus of both species contains a mixture of striated and smooth muscle. This conserved architecture enhances the translational relevance of studies performed in mouse models. We identified dual roles for ICC-IM in regulating phasic contractility in the distal esophagus and tone in the LES via a Ca2+ activated Cl- channel, ANO1. Notably, we described a subpopulation of ICC-IM with a unique Ca2+ signaling behavior that appears to underlie rhythmicity in the distal esophagus; this population is absent in the tone generating LES. We also demonstrate that ICC-IM mediate cholinergic and nitrergic neurotransmission directly by altering intracellular Ca2+ signaling, thereby altering ANO1 activity. We show that PDGFRα+ cells express purinergic receptors and small conductance Ca2+ activated K+ channels (SK3) despite the apparent lack of a functional purinergic neural input. We demonstrate that these purinergic receptors can however be activated pharmacologically suggesting that this pathway may become active in disease whereby there is an increase in LES relaxation. Interstitial cells were often closely associated with nerve fibers throughout the entire esophagus and LES and may regulate neurotransmission in proximal regions in a manner similar to what we show for the LES. Together, the data presented in this dissertation outlines a multifaceted role for interstitial cells in coordinating esophageal motility and neurotransmission. Alterations in these pathways may contribute to motility disorders such as achalasia and gastroesophageal reflux disease, and the identification of ion channel signaling mechanisms (e.g., ANO1) highlights potential therapeutic targets for the development of less invasive, pharmacological treatments for esophageal disease.