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American Journal of Physiology.... Nov 2023Notch signaling regulates gastrointestinal stem cell proliferation and differentiation yet Notch-regulated transcriptional effectors of gastric epithelial cell...
Notch signaling regulates gastrointestinal stem cell proliferation and differentiation yet Notch-regulated transcriptional effectors of gastric epithelial cell differentiation are poorly understood. Here we tested the role of the bHLH transcription factor Achaete-Scute homolog 1 (ASCL1) in gastric epithelial cell differentiation, and its regulation by Notch. Newborn null mice showed a loss of expression of markers of neurogenin-3-dependent enteroendocrine cells, with normal expression of enterochromaffin-like cells, mucous cells, chief cells, and parietal cells. In adult mice, gene expression was observed in the stomach, but not the intestine, with higher expression in antral than corpus epithelium. Lineage tracing in mice revealed single, scattered ASCL1 cells in the gastric epithelium, demonstrating expression in antral gastrin- and serotonin-producing endocrine cells. ASCL1-expressing endocrine cells persisted for several weeks posttamoxifen labeling with a half-life of approximately 2 months. Lineage tracing in mice demonstrated a similar lifespan for gastrin-producing cells, confirming that gastric endocrine cells are long-lived. Finally, treatment of ; mice with the pan-Notch inhibitor dibenzazepine increased the number of lineage-labeled cells in the gastric antrum, suggesting that Notch signaling normally inhibits expression. Notch regulation of was also demonstrated in a genetic mouse model of Notch activation, as well as Notch-manipulated antral organoid cultures, thus suggesting that ASCL1 is a key downstream Notch pathway effector promoting endocrine cell differentiation in the gastric epithelium. Although Notch signaling is known to regulate cellular differentiation in the stomach, downstream effectors are poorly described. Here we demonstrate that the bHLH transcription factor ASCL1 is expressed in endocrine cells in the stomach and is required for formation of neurogenin-3-dependent enteroendocrine cells but not enterochromaffin-like cells. We also demonstrate that expression is inhibited by Notch signaling, suggesting that ASCL1 is a Notch-regulated transcriptional effector directing enteroendocrine cell fate in the mouse stomach.
Topics: Animals; Mice; Basic Helix-Loop-Helix Transcription Factors; Cell Differentiation; Enteroendocrine Cells; Gastrins; Mice, Knockout; Stomach
PubMed: 37698169
DOI: 10.1152/ajpgi.00043.2023 -
World Journal of Gastrointestinal... Aug 2023The molecular changes present in gastric neuroendocrine tumors (NETs) include a loss of heterozygosity or mutation of , gene mutation, heterozygous mutation, and gene...
BACKGROUND
The molecular changes present in gastric neuroendocrine tumors (NETs) include a loss of heterozygosity or mutation of , gene mutation, heterozygous mutation, and gene missense mutation. We identified and are the first to report a case of type 1 histamine-producing enterochromaffin-like cell NETs (ECL-cell NETs) with a gene germline mutation.
CASE SUMMARY
The patient had a history of iron-deficient anemia for 5 years, and gastroscopic examination indicated multiple gastric tumors. Then, the patient underwent distal gastrectomy. Microscopically, multifocal tumor cells were found in the mucosa and submucosa; tumor cells were organoid and arranged in nests and cords, and the stroma was rich in sinusoids. The surrounding gastric mucosa showed atrophy with mild intestinal metaplasia or pseudopyloric gland metaplasia. Neuroendocrine cells could be seen with diffuse linear, nodular, and adenomatous hyperplasia. Immunohistochemically, the tumor cells diffusely expressed cytokeratin, chromogranin, synaptophysin, and CD56. Whole-genome high-throughput molecular sequencing revealed a pathogenic germline mutation in the gene, a heterozygous germline frameshift mutation in exon 11, c.6443_6444del (p.S2148Yfs*2). The final diagnosis was gastric type 1 ECL-cell NETs with a gene germline mutation, accompanied by autoimmune gastritis.
CONCLUSION
This is the first report of a case of type 1 gastric ECL-cell NETs with a pathogenic germline mutation of the gene. The findings of this report will expand the germline mutation spectrum of gastric NETs and increase the understanding of the molecular changes present in these tumors for their improved diagnosis in the future.
PubMed: 37663942
DOI: 10.4251/wjgo.v15.i8.1497 -
BioRxiv : the Preprint Server For... Aug 2023Dynamic interactions between gut mucosal cells and the external environment are essential to maintain gut homeostasis. Enterochromaffin (EC) cells transduce both...
Dynamic interactions between gut mucosal cells and the external environment are essential to maintain gut homeostasis. Enterochromaffin (EC) cells transduce both chemical and mechanical signals and produce 5-hydroxytryptamine (5-HT) to mediate disparate physiological responses. However, the molecular and cellular basis for functional diversity of ECs remains to be adequately defined. Here, we integrated single-cell transcriptomics with spatial image analysis to identify fourteen EC clusters that are topographically organized along the gut. Subtypes predicted to be sensitive to the chemical environment and mechanical forces were identified that express distinct transcription factors and hormones. A population in the distal colon was endowed with a distinctive neuronal signature. Using a combination of genetic, chemogenetic and pharmacological approaches, we demonstrated ECs are required for normal colon motility. Our study constructs a molecular map for ECs and offers a framework for deconvoluting EC cells with pleiotropic functions.
PubMed: 37662229
DOI: 10.1101/2023.08.24.554649 -
Pharmacological Reports : PR Oct 2023The neural mechanisms and the receptors behind the course of chemotherapy-induced nausea and vomiting (CINV) are well described and considered mechanistically... (Review)
Review
The neural mechanisms and the receptors behind the course of chemotherapy-induced nausea and vomiting (CINV) are well described and considered mechanistically multifactorial, whereas the neurobiology of nausea is not completely understood yet. Some of the anti-neoplastic medications like cisplatin result in biphasic vomiting response. The acute phase of vomiting is triggered mainly via the release of serotonin from the enterochromaffin (EC) cells in the gastrointestinal tract (GIT) and results in stimulation of dorsal vagal complex (DVC) of the vomiting center and the vomiting is initiated by downward communication to the gut via vagal efferents. Agonism of 5HT receptors is majorly involved in the mediation of the acute phase. Therefore, antagonists at 5HT receptors are effective in the management of acute-phase vomiting episodes. Likewise, Dopamine type 2 (D) receptors, dopamine neurotransmitter, Muscarinic receptors (M), GLP receptors, and histaminergic receptors (H) are also implicated in the vomiting act as well. In continuation, Cannabinoid type 1 (CB) receptors are also recommended and included in the guidelines as agonism of presynaptically located CB receptors inhibits the release of excitatory neurotransmitters responsible for vomiting initiation. The delayed phase involves the release of "Substance P" in the gut and results in the stimulation of neurokinin-1 (NK) receptors centrally in the area postrema (AP) and nucleus tractus solitarius (NTS), subsequently the vomiting response. The current understanding is the existence of overlapping mechanisms of neurotransmitters, serotonin, dopamine, and substance P throughout the time course of CINV. Furthermore, the emetic neurotransmitters are released via calcium ion (Ca)-dependent mechanisms, implicating the molecular targets of intracellular Ca signaling in emetic circuitry. The current review entails the neurobiology of nausea and vomiting induced by cancer chemotherapeutic agents and the recent approaches in the management.
Topics: Humans; Emetics; Serotonin; Dopamine; Vomiting; Nausea; Antineoplastic Agents; Neurotransmitter Agents; Antiemetics
PubMed: 37584820
DOI: 10.1007/s43440-023-00514-z -
Journal of Animal Science and... Aug 2023Serotonin is an important signaling molecule that regulates secretory and sensory functions in the gut. Gut microbiota has been demonstrated to affect serotonin...
BACKGROUND
Serotonin is an important signaling molecule that regulates secretory and sensory functions in the gut. Gut microbiota has been demonstrated to affect serotonin synthesis in rodent models. However, how gut microbes regulate intestinal serotonin production in piglets remains vague. To investigate the relationship between microbiota and serotonin specifically in the colon, microbial composition and serotonin concentration were analyzed in ileum-cannulated piglets subjected to antibiotic infusion from the ileum when comparing with saline infusion. Microbes that correlated positively with serotonin production were isolated from piglet colon and were further used to investigate the regulation mechanisms on serotonin production in IPEC-J2 and a putative enterochromaffin cell line RIN-14B cells.
RESULTS
Antibiotic infusion increased quantities of Lactobacillus amylovorus (LA) that positively correlated with increased serotonin concentrations in the colon, while no effects observed for Limosilactobacillus reuteri (LR). To understand how microbes regulate serotonin, representative strains of LA, LR, and Streptococcus alactolyticus (SA, enriched in feces from prior observation) were selected for cell culture studies. Compared to the control group, LA, LR and SA supernatants significantly up-regulated tryptophan hydroxylase 1 (TPH1) expression and promoted serotonin production in IPEC-J2 cells, while in RIN-14B cells only LA exerted similar action. To investigate potential mechanisms mediated by microbe-derived molecules, microbial metabolites including lactate, acetate, glutamine, and γ-aminobutyric acid were selected for cell treatment based on computational and metabolite profiling in bacterial supernatant. Among these metabolites, acetate upregulated the expression of free fatty acid receptor 3 and TPH1 while downregulated indoleamine 2,3-dioxygenase 1. Similar effects were also recapitulated when treating the cells with AR420626, an agonist targeting free fatty acid receptor 3.
CONCLUSIONS
Overall, these results suggest that Lactobacillus amylovorus showed a positive correlation with serotonin production in the pig gut and exhibited a remarkable ability to regulate serotonin production in cell cultures. These findings provide evidence that microbial metabolites mediate the dialogue between microbes and host, which reveals a potential approach using microbial manipulation to regulate intestinal serotonin biosynthesis.
PubMed: 37542282
DOI: 10.1186/s40104-023-00903-7 -
Cell Reports Methods Jul 2023Time-specific modulation of gene expression during differentiation by transcription factors promotes cell diversity. However, estimating their dynamic regulatory...
Time-specific modulation of gene expression during differentiation by transcription factors promotes cell diversity. However, estimating their dynamic regulatory activity at the single-cell level and in a high-throughput manner remains challenging. We present FateCompass, an integrative approach that utilizes single-cell transcriptomics data to identify lineage-specific transcription factors throughout differentiation. By combining a probabilistic framework with RNA velocities or differentiation potential, we estimate transition probabilities, while a linear model of gene regulation is employed to compute transcription factor activities. Considering dynamic changes and correlations of expression and activities, FateCompass identifies lineage-specific regulators. Our validation using data and application to pancreatic endocrine cell differentiation datasets highlight both known and potentially novel lineage-specific regulators. Notably, we uncovered undescribed transcription factors of an enterochromaffin-like population during differentiation toward ß-like cells. FateCompass provides a valuable framework for hypothesis generation, advancing our understanding of the gene regulatory networks driving cell-fate decisions.
Topics: Transcription Factors; Cell Differentiation; Gene Expression Regulation; Gene Regulatory Networks; Gene Expression Profiling
PubMed: 37533652
DOI: 10.1016/j.crmeth.2023.100512 -
Neuroscience Bulletin Nov 2023
Topics: Humans; Enterochromaffin Cells
PubMed: 37458959
DOI: 10.1007/s12264-023-01090-1 -
Internal and Emergency Medicine Sep 2023The intestinal mucosa represents the most extensive human barrier having a defense function against microbial and food antigens. This barrier is represented externally... (Review)
Review
The intestinal mucosa represents the most extensive human barrier having a defense function against microbial and food antigens. This barrier is represented externally by a mucus layer, consisting mainly of mucins, antimicrobial peptides, and secretory immunoglobulin A (sIgA), which serves as the first interaction with the intestinal microbiota. Below is placed the epithelial monolayer, comprising enterocytes and specialized cells, such as goblet cells, Paneth cells, enterochromaffin cells, and others, each with a specific protective, endocrine, or immune function. This layer interacts with both the luminal environment and the underlying lamina propria, where mucosal immunity processes primarily take place. Specifically, the interaction between the microbiota and an intact mucosal barrier results in the activation of tolerogenic processes, mainly mediated by FOXP3 regulatory T cells, underlying intestinal homeostasis. Conversely, the impairment of the mucosal barrier function, the alteration of the normal luminal microbiota composition (dysbiosis), or the imbalance between pro- and anti-inflammatory mucosal factors may result in inflammation and disease. Another crucial component of the intestinal barrier is the gut-vascular barrier, formed by endothelial cells, pericytes, and glial cells, which regulates the passage of molecules into the bloodstream. The aim of this review is to examine the various components of the intestinal barrier, assessing their interaction with the mucosal immune system, and focus on the immunological processes underlying homeostasis or inflammation.
Topics: Humans; Immunity, Mucosal; Endothelial Cells; Intestinal Mucosa; Inflammation; Homeostasis
PubMed: 37402104
DOI: 10.1007/s11739-023-03329-1 -
Yakugaku Zasshi : Journal of the... 2023The nausea and vomiting that occur as a result of oral iron administration for the treatment of iron-deficiency anemia (IDA) can cause significant physical and emotional... (Review)
Review
The nausea and vomiting that occur as a result of oral iron administration for the treatment of iron-deficiency anemia (IDA) can cause significant physical and emotional stress in patients. Because iron is absorbed from the intestine as ferrous iron, the most widely used treatment for IDA is oral ferrous agents. However, ferrous forms are more toxic than ferric forms because ferrous forms readily generate free radicals. A randomized, double-blind, active-controlled, multicenter non-inferiority study conducted in Japan showed that ferric citrate hydrate (FC) was just as effective as sodium ferrous citrate (SF) in the treatment of IDA, with a lower incidence of adverse reactions such as nausea and vomiting compared with SF. Animal studies have shown that chemotherapy-induced nausea and vomiting (CINV) involves the release of 5-hydroxytryptamine from enterochromaffin cells by free radicals, and that some chemotherapeutic agents cause hyperplasia of these cells. Enterochromaffin cells also contain substance P, which is known to be also closely related to CINV. We found that administration of SF to rats causes hyperplasia of enterochromaffin cells in the small intestine, whereas FC has no effect on enterochromaffin cells. Oral iron agents may induce nausea and vomiting via the effect of ferrous iron on reactive oxygen species production in the intestine and subsequent enterochromaffin cell hyperplasia. Further research to elucidate the detailed mechanism of enterochromaffin cell hyperplasia induced by ferrous iron preparations is needed to develop a treatment for iron deficiency anemia that causes less gastrointestinal damage.
Topics: Animals; Rats; Anemia, Iron-Deficiency; Ferric Compounds; Hyperplasia; Iron; Nausea; Vomiting
PubMed: 37394455
DOI: 10.1248/yakushi.23-00057