Anatomy and Neuroscience - Theses
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ItemDistinguishing features and regulatory roles of 5-HT containing enteroendocrine cells( 2022)Enteroendocrine cells (EEC) have important roles in communicating the state of the gastrointestinal (GI) tract to the rest of the body, and in signalling within the GI tract. They signal in response to nutrients and metabolites in the GI tract, potentially toxic compounds and mechanical forces. The most numerous EEC signal through 5-hydroxytryptamine (5-HT; also known as serotonin). These were also the first EEC to be identified, which was through their reactions with chrome salts, from which they gained the name enterochromaffin (EC) cells. It was at first thought that all 5-HT producing EEC were much the same. In the recent years, it has become apparent that there are functionally diverse subtypes of 5-HT containing EEC. EEC make up only approximately 1% of the intestinal epithelial cells but they are responsible for producing more than 20 peptide hormones. Of the 1% EEC population, EC cells are the most abundant cell type. I have shown that 5-HT containing EEC co-express a variety of gut hormones (Chapter 2), and their co-expression patterns are defining features that characterise them into various subpopulations based on the hormones they produce. Furthermore, EEC subpopulations express a collection of receptors that respond to different stimuli which impact their physiological effects, thus adding another layer of complexity when classifying the functional subtypes of EEC. 5-HT cells are generally depicted to be open flask-shape cells in the literature. However, one study showed an intriguing characteristic of long basal processes exhibited by some EC cells, though no study had characterised the distinct morphology of 5-HT cells in detail. Therefore, I have undertaken extensive investigations to document the morphological characteristics of 5-HT cells from the mouse stomach to rectum (Chapter 3 and Appendix A). Approximately 50% of 5-HT cells in the mouse distal colon had long basal processes, and this morphology was also observed in the gastric antrum and the rectum. These processes can reach 100 micron in length, and the abundance of this structure must serve some functional roles in the intestinal mucosa. I speculate on these in Chapters 3 and 7, and in Appendix A. An unanswered question arising from the complexity of hormone co-expression is whether co-expressed hormones could be differentially released. To address this, I examined the subcellular distribution of 5-HT and tachykinin (TK) storing secretory vesicles within the same EEC (Chapter 4). 5-HT and TK are stored in separate vesicles, and the two pools of vesicles were preferentially translocated when stimulated with glucose. In addition, duodenal 5-HT/TK cells responded differently than colonic 5-HT/TK cells under the same stimulated condition, suggesting a regional difference of EEC subpopulations. Insulin-like peptide 5 (INSL5) is co-expressed with GLP-1 and PYY in colonic L cells, and I discovered that some 5-HT cells had an intertwining relationship with L cells in the mouse large intestine (Chapter 3). In Chapter 5, I describe the development of an LC/MS assay for an INSL5 analogue that I used to investigate the role of INSL5 (Appendix B). I also discovered that RXFP4, a natural receptor for INSL5, is extensively expressed by colonic 5-HT cells and by some sensory nerve fibres in the mucosa, submucosa, and the muscle layers of the large intestine (Chapter 6). Hence, INSL5 could have an effect on both RXFP4 expressing nerve terminals and on neighbouring 5-HT cells. The regulatory role of 5-HT in the control of colorectal propulsion was demonstrated to be through an INSL5/RXFP4/5-HT/5-HT3R neuro-endocrine circuit. Collectively, my studies presented in this thesis have systematically defined the distinguishing features of 5-HT containing EEC throughout the GI tract and the regulatory role of 5-HT in colonic motility.