Neuropods
2019; Elsevier BV; Volume: 7; Issue: 4 Linguagem: Inglês
10.1016/j.jcmgh.2019.01.006
ISSN2352-345X
Autores Tópico(s)Helicobacter pylori-related gastroenterology studies
ResumoEnteroendocrine cells (EECs) are sensory cells of the gastrointestinal tract. Most EECs reside in the mucosal lining of the stomach or intestine and sense food in the gut lumen. Food signals stimulate the release of hormones into the paracellular space where they either act locally or are taken up into the blood and circulate to distant organs. It recently was recognized that many EECs possess basal processes known as neuropods that not only contain hormones but also connect to nerves. This review describes how neuropods contribute to EEC function beyond typical hormonal actions. For example, gastrointestinal hormones not only act on distant organs, but, through neuropods, some act locally to stimulate other mucosal cells such as intestinal stem cells, enterocytes, or other EECs. With the recent discovery that EECs communicate directly with enteric nerves, EECs not only have the ability to sense food and bacteria in the gastrointestinal tract, but can communicate these signals directly to the nervous system. Enteroendocrine cells (EECs) are sensory cells of the gastrointestinal tract. Most EECs reside in the mucosal lining of the stomach or intestine and sense food in the gut lumen. Food signals stimulate the release of hormones into the paracellular space where they either act locally or are taken up into the blood and circulate to distant organs. It recently was recognized that many EECs possess basal processes known as neuropods that not only contain hormones but also connect to nerves. This review describes how neuropods contribute to EEC function beyond typical hormonal actions. For example, gastrointestinal hormones not only act on distant organs, but, through neuropods, some act locally to stimulate other mucosal cells such as intestinal stem cells, enterocytes, or other EECs. With the recent discovery that EECs communicate directly with enteric nerves, EECs not only have the ability to sense food and bacteria in the gastrointestinal tract, but can communicate these signals directly to the nervous system. SummaryEnteroendocrine cells (EECs) are sensory cells of the gut that communicate by releasing hormones locally through paracrine action or into the blood stream. Recently it has been discovered that EECs possess cytoplasmic processes known as neuropods that extend to distant cells including nerves. Thus, EECs regulate ingestive behavior through local, hormonal and neural signaling. Enteroendocrine cells (EECs) are sensory cells of the gut that communicate by releasing hormones locally through paracrine action or into the blood stream. Recently it has been discovered that EECs possess cytoplasmic processes known as neuropods that extend to distant cells including nerves. Thus, EECs regulate ingestive behavior through local, hormonal and neural signaling. Traditionally, enteroendocrine cells (EECs) have been viewed as spindle or flask-shaped cells that reside in the mucosa of the gastrointestinal tract.1Solcia E. Capella C. Buffa R. Usellini L. Frigerio B. Fontana P. Endocrine cells of the gastrointestinal tract and related tumors.Pathobiol Annu. 1979; 9: 163-204PubMed Google Scholar, 2Solcia E. Usellini L. Buffa R. Rindi G. Villani L. Zampatti C. Silini E. Endocrine cells producing regulatory peptides.Experientia. 1987; 43: 839-850Crossref PubMed Scopus (28) Google Scholar Most EECs are open to the intestinal lumen where a small portion of their apical surface is exposed to intestinal contents. Similar to enterocytes, microvilli cover their luminal surface. In this manner, EECs can sample food or microbes in the intestine. A small number of EECs are of the closed type, and even though their cell bodies are contained in the mucosa, they do not come into contact with the lumen of the intestine. Hormones are stored within vesicles that are concentrated in the basal region of the EEC and are released into the paracellular space when the cell is stimulated. Secreted hormones can act locally on adjacent cells or be taken up by the blood stream where they can bind to cell surface receptors on distant organs.3Wade P.R. Westfall J.A. Ultrastructure of enterochromaffin cells and associated neural and vascular elements in the mouse duodenum.Cell Tissue Res. 1985; 241: 557-563Crossref PubMed Scopus (41) Google Scholar In this manner, EECs can sense gut contents and communicate these signals throughout the body. Most EECs have been identified through their expression of a predominant gastrointestinal peptide and were assigned a single letter designation.4Helander H.F. Fandriks L. The enteroendocrine "letter cells" - time for a new nomenclature?.Scand J Gastroenterol. 2012; 47: 3-12Crossref PubMed Scopus (22) Google Scholar For example, in the stomach, gastrin-containing cells were called G cells, while somatostatin cells, whether they are found in the stomach or pancreatic islets, have been referred to as D cells. With the exception of L cells, which produce both peptide YY (PYY) and glucagon-like peptides (GLPs), it was believed that a single EEC produced only 1 peptide hormone. Recently, however, using mice with transgenic expression of fluorescent markers, it has been shown that EECs previously thought to express only a single hormone actually produce many gastrointestinal peptides.5Haber A.L. Biton M. Rogel N. Herbst R.H. Shekhar K. Smillie C. Burgin G. Delorey T.M. Howitt M.R. Katz Y. Tirosh I. Beyaz S. Dionne D. Zhang M. Raychowdhury R. Garrett W.S. Rozenblatt-Rosen O. Shi H.N. Yilmaz O. Xavier R.J. Regev A. A single-cell survey of the small intestinal epithelium.Nature. 2017; 551: 333-339Crossref PubMed Scopus (711) Google Scholar In fact, it appears that secretin is expressed in most, if not all, EECs of the intestine.5Haber A.L. Biton M. Rogel N. Herbst R.H. Shekhar K. Smillie C. Burgin G. Delorey T.M. Howitt M.R. Katz Y. Tirosh I. Beyaz S. Dionne D. Zhang M. Raychowdhury R. Garrett W.S. Rozenblatt-Rosen O. Shi H.N. Yilmaz O. Xavier R.J. Regev A. A single-cell survey of the small intestinal epithelium.Nature. 2017; 551: 333-339Crossref PubMed Scopus (711) Google Scholar Thus, not only is the terminology for describing specific EECs incomplete, the diversity of EECs is wider than ever expected. The variety of hormones expressed in EECs has broad implications for the function of these cells that is only beginning to be explored. For the purposes of this review, we refer to EECs by the hormone(s) they produce. Within the gastrointestinal tract, the anatomy of EECs has been guided largely through microscopic analysis of tissues stained for chemical properties such as silver (eg, argentaffin), or immunohistochemical staining using general vesicle markers (eg, chromogranin) or specific hormone antibodies.6Grimelius L. Methods in neuroendocrine histopathology, a methodological overview.Ups J Med Sci. 2008; 113: 243-260Crossref PubMed Scopus (9) Google Scholar These methods have shown that EECs comprise approximately 1% of the intestinal mucosal cells, are dispersed among enterocytes, and contain secretory vesicles along their basal pole. Electron microscopy has shown that microvilli cover the luminal surface of EECs and that both electron-dense core vesicles typical of hormone-containing granules and clear vesicles resembling neurotransmitter-containing granules comprise the vesicular compartment of EECs.2Solcia E. Usellini L. Buffa R. Rindi G. Villani L. Zampatti C. Silini E. Endocrine cells producing regulatory peptides.Experientia. 1987; 43: 839-850Crossref PubMed Scopus (28) Google Scholar Because traditional microscopy generally is performed in 2 dimensions, it has been difficult to appreciate all of the anatomic features of EECs that deviate from the traditional spindle or flask-shape view. The exception has been somatostatin-containing cells of the stomach.7Larsson L.I. Goltermann N. de Magistris L. Rehfeld J.F. Schwartz T.W. Somatostatin cell processes as pathways for paracrine secretion.Science. 1979; 205: 1393-1395Crossref PubMed Scopus (398) Google Scholar Somatostatin, which has broad inhibitory effects, is found in gastric cells that have long cytoplasmic processes that extend to adjacent gastrin-producing EECs and hydrochloric acid–producing parietal cells. Thus, it appeared that somatostatin could be delivered to and released from cytoplasmic processes. This discovery provided compelling evidence for paracrine control of cell function in the gastrointestinal tract.8Larsson L.I. Peptide secretory pathways in GI tract: cytochemical contributions to regulatory physiology of the gut.Am J Physiol. 1980; 239: G237-G246PubMed Google Scholar It was assumed that paracrine effects made manifest through cytoplasmic extensions were unique to somatostatin cells and were most apparent in the stomach despite several curious observations. Serotonin-containing enterochromaffin cells, a subtype of EECs, also are believed to exert paracrine effects within the gastrointestinal tract. By using immunohistochemical staining and careful cell dissection techniques, a physical connection was observed between EECs and other cells through an axon-like process.9Gustafsson B.I. Bakke I. Tommeras K. Waldum H.L. A new method for visualization of gut mucosal cells, describing the enterochromaffin cell in the rat gastrointestinal tract.Scand J Gastroenterol. 2006; 41: 390-395Crossref PubMed Scopus (28) Google Scholar However, the presence of such processes was not limited to somatostatin cells.10Sjolund K. Sanden G. Hakanson R. Sundler F. Endocrine cells in human intestine: an immunocytochemical study.Gastroenterology. 1983; 85: 1120-1130Abstract Full Text PDF PubMed Scopus (416) Google Scholar In the intestine, mucosal cells arise from crypt stem cells and migrate toward the lumen. Within 4–5 days most mucosal cells reach the villus tip, undergo apoptosis, and are sloughed into the intestinal lumen. Although it was observed that an occasional EEC of the distal small intestine possessed a lagging segment of cytoplasm along the basal surface, it was assumed this occurred as the EEC was being pushed upward by younger cells arising from the crypt.11Cheng H. Leblond C.P. Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. III. Entero-endocrine cells.Am J Anat. 1974; 141: 503-519Crossref PubMed Scopus (245) Google Scholar Even though this explanation seems unlikely because lagging cytoplasm has not been observed for other migrating mucosal cells such as enterocytes or goblet cells, it largely has gone unchallenged. With the development of transgenic mice expressing green fluorescent protein (GFP) downstream from the specific gastrointestinal hormone promoters such as cholecystokinin (CCK) and PYY, EECs could be analyzed using confocal fluorescence microscopy.12Chandra R. Samsa L.A. Vigna S.R. Liddle R.A. Pseudopod-like basal cell processes in intestinal cholecystokinin cells.Cell Tissue Res. 2010; 341: 289-297Crossref PubMed Scopus (32) Google Scholar, 13Bohórquez D.V. Liddle R.A. Axon-like basal processes in enteroendocrine cells: characteristics and potential targets.Clin Transl Sci. 2011; 4: 387-391Crossref PubMed Scopus (29) Google Scholar With the ability to visualize cells in 3 dimensions, it was possible to trace cellular processes that extended outside a simple plane. Remarkably, a large number of EECs from the proximal small intestine of CCK-GFP mice showed basal cytoplasmic processes. These processes generally extended from the basal portion of the cell but occasionally arose from the midportion of the cell body. They were usually less than 10 μm in length and radiated in all directions from the EEC. Their multidirectionality clearly differed from the unidirectional cytoplasmic processes reported previously and were not consistent with the notion that they were caused by EECs being pushed toward the villus tip. However, where these cytoplasmic processes went and what they did was not known. In contrast to CCK cells in the proximal small intestine, PYY cells had only 1 process per cell, although they often were much longer, with some extending over 70 μm in length. Long cytoplasmic processes tunneled under enterocytes along the lamina propria (Figure 1). How to assess the ultrastructure of EECs that contained long cytoplasmic extensions posed a formidable problem. First, it was difficult to locate a rare cell type (an EEC) among a field of enterocytes and other mucosal cells using traditional electron microscopy. Second, by its very nature, electron microscopy is ideal for analyzing a small region of a cell, but does not lend itself to tracing a long and possibly tortuous cellular process that may not reside in a single plane. To circumvent these problems, confocal microscopy was used to locate a fluorescent EEC combined with a newly developed technique of 3-dimensional scanning electron microscopy.14Bohórquez D.V. Samsa L.A. Roholt A. Medicetty S. Chandra R. Liddle R.A. An enteroendocrine cell-enteric glia connection revealed by 3D electron microscopy.PLoS One. 2014; 9: e89881Crossref PubMed Scopus (138) Google Scholar This approach enabled imaging an entire EEC with its cytoplasmic process from the distal small intestine. Several unique features of the cytoplasmic process were revealed. First, 70% of the EEC's secretory vesicles were contained within the process. Second, both small, clear and large, dense core vesicles were identified. Third, the process was packed with mitochondria. Fourth, running down the core of the process was a ribbon-like band absent of ribosomes that upon immunohistochemical staining was found to contain neurofilament proteins, the structural component of neuronal axons. Finally, this axon-like process came into contact with glia in the submucosa. These findings indicated that EECs possess many neuron-like properties and the cytoplasmic process became known as a neuropod (Figure 2).Figure 2Enteroendocrine cell communication within the gut. A model of an enteroendocrine cell (green) residing in the epithelium of the gut shows that EECs contain both large, dense (blue) and small, clear (yellow) secretory granules that are believed to contain peptide hormones (eg, CCK, PYY, and GLPs) and neurotransmitters (eg, glutamate), respectively. Neurotransmitters are released at synaptic connections with sensory neurons. Peptides such as PYY or GLP-2 are released locally and bind to proliferative cells in the crypt or intestinal subepithelial myofibroblasts, respectively. Peptides (eg, CCK, PYY, and GLPs) also may bind locally to nerves.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The prototypical paracrine cell is the somatostatin-containing D cell found in the intestine and pancreatic islets. In the gut, somatostatin cells were notable for their dendritic-like processes that extended to adjacent cells, including other EECs.7Larsson L.I. Goltermann N. de Magistris L. Rehfeld J.F. Schwartz T.W. Somatostatin cell processes as pathways for paracrine secretion.Science. 1979; 205: 1393-1395Crossref PubMed Scopus (398) Google Scholar The dictum that structure determines function was keenly illustrated by somatostatin cells when it was recognized that the broad inhibitory actions of somatostatin were not well suited for precise control of individual cells. In contrast, when cellular extensions were seen to innervate other cells it was easy to appreciate that somatostatin could be delivered at a specific site. Thus, the cellular processes on somatostatin cells are ideal for targeted delivery of a transmitter onto a single cell. In the stomach, cellular processes extend from the cell body of D cells through which somatostatin exerts a tonic inhibitory action on gastrin-containing cells to block gastrin release in the antrum.15Makhlouf G.M. Schubert M.L. Gastric somatostatin: a paracrine regulator of acid secretion.Metabolism. 1990; 39: 138-142Abstract Full Text PDF PubMed Scopus (59) Google Scholar From somatostatin cells in the body and fundus of the stomach, cellular processes extend to parietal cells to directly inhibit gastric acid secretion.16Schubert M.L. Edwards N.F. Arimura A. Makhlouf G.M. Paracrine regulation of gastric acid secretion by fundic somatostatin.Am J Physiol. 1987; 252: G485-G490PubMed Google Scholar Dual feedback loops regulate somatostatin cell function. First, somatostatin cells that are open to the gastric lumen are stimulated by gastric acid. Somatostatin released from these cells then inhibits both G cells and parietal cells to reduce gastrin and gastric acid secretion. Second, somatostatin cells possess gastrin (CCK2) receptors, activation of which also stimulates somatostatin release, resulting in reduced gastrin and acid secretion.17DelValle J. Chiba T. Park J. Yamada T. Distinct receptors for cholecystokinin and gastrin on canine fundic D-cells.Am J Physiol. 1993; 264: G811-G815PubMed Google Scholar GLP-1 and GLP-2 are synthesized in L cells, which are most abundant in the ileum and colon.18Drucker D.J. Habener J.F. Holst J.J. Discovery, characterization, and clinical development of the glucagon-like peptides.J Clin Invest. 2017; 127: 4217-4227Crossref PubMed Scopus (190) Google Scholar These are the same cells that produce PYY. It is believed that stimulation of L cells causes the release of all 3 peptides. GLP-1 and GLP-2 are products of post-translational processing of the prohormone proglucagon. GLP-1 and GLP-2 are secreted in response to ingested nutrients, including glucose and fat, and their main biological actions are to enhance insulin secretion and intestinal epithelial growth, respectively.19Holst J.J. Enteroglucagon. 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Thus, it appears that L cells release GLP-2, which stimulates iSEMFs to produce IGF-1 and EGF, which exert their own paracrine effects on the intestinal muc
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