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International Journal of Stem Cells Aug 2023The colonic epithelial layer is a complex structure consisting of multiple cell types that regulate various aspects of colonic physiology, yet the mechanisms underlying...
BACKGROUND AND OBJECTIVES
The colonic epithelial layer is a complex structure consisting of multiple cell types that regulate various aspects of colonic physiology, yet the mechanisms underlying epithelial cell differentiation during development remain unclear. Organoids have emerged as a promising model for investigating organogenesis, but achieving organ-like cell configurations within colonic organoids is challenging. Here, we investigated the biological significance of peripheral neurons in the formation of colonic organoids.
METHODS AND RESULTS
Colonic organoids were co-cultured with human embryonic stem cell (hESC)-derived peripheral neurons, resulting in the morphological maturation of columnar epithelial cells, as well as the presence of enterochromaffin cells. Substance P released from immature peripheral neurons played a critical role in the development of colonic epithelial cells. These findings highlight the vital role of inter-organ interactions in organoid development and provide insights into colonic epithelial cell differentiation mechanisms.
CONCLUSIONS
Our results suggest that the peripheral nervous system may have a significant role in the development of colonic epithelial cells, which could have important implications for future studies of organogenesis and disease modeling.
PubMed: 37385635
DOI: 10.15283/ijsc23026 -
Comprehensive Physiology Jun 2023Although it is most well-known for its roles in central nervous system (CNS) function, the vast majority of serotonin, or 5-hydroxytryptamine (5-HT), is produced in the...
Although it is most well-known for its roles in central nervous system (CNS) function, the vast majority of serotonin, or 5-hydroxytryptamine (5-HT), is produced in the gastrointestinal (GI) tract. 5-HT is synthesized mostly by enterochromaffin (EC) cells of the GI epithelium and, in small part, by neurons of the enteric nervous system (ENS). The GI tract contains an array of broadly distributed 5-HT receptors, which participate in functions such as motility, sensation, inflammation, and neurogenesis. The roles of 5-HT in these functions are reviewed, as well as its role in the pathophysiology of disorders of gut-brain interaction (DGBIs) and inflammatory bowel diseases (IBD). © 2023 American Physiological Society. Compr Physiol 13:4851-4868, 2023.
Topics: Humans; Serotonin; Gastrointestinal Motility; Receptors, Serotonin; Inflammation; Gastrointestinal Tract
PubMed: 37358510
DOI: 10.1002/cphy.c220024 -
Immunity Jul 2023The crosstalk between the immune and neuroendocrine systems is critical for intestinal homeostasis and gut-brain communications. However, it remains unclear how immune...
The crosstalk between the immune and neuroendocrine systems is critical for intestinal homeostasis and gut-brain communications. However, it remains unclear how immune cells participate in gut sensation of hormones and neurotransmitters release in response to environmental cues, such as self-lipids and microbial lipids. We show here that lipid-mediated engagement of invariant natural killer T (iNKT) cells with enterochromaffin (EC) cells, a subset of intestinal epithelial cells, promoted peripheral serotonin (5-HT) release via a CD1d-dependent manner, regulating gut motility and hemostasis. We also demonstrated that inhibitory sphingolipids from symbiotic microbe Bacteroides fragilis represses 5-HT release. Mechanistically, CD1d ligation on EC cells transduced a signal and restrained potassium conductance through activation of protein tyrosine kinase Pyk2, leading to calcium influx and 5-HT secretion. Together, our data reveal that by engaging with iNKT cells, gut chemosensory cells selectively perceive lipid antigens via CD1d to control 5-HT release, modulating intestinal and systemic homeostasis.
Topics: Serotonin; Lipids; Antigens, CD1d; Natural Killer T-Cells
PubMed: 37354904
DOI: 10.1016/j.immuni.2023.06.001 -
Regulatory Toxicology and Pharmacology... Aug 2023Tegoprazan is a novel potassium-competitive acid blocker (P-CAB) that reversibly inhibits the proton pump in gastric parietal cells and has been approved for the...
Tegoprazan is a novel potassium-competitive acid blocker (P-CAB) that reversibly inhibits the proton pump in gastric parietal cells and has been approved for the treatment of acid-related diseases in Korea. This study aimed to evaluate the carcinogenic potential of tegoprazan in Sprague-Dawley rats and CD-1 mice. Tegoprazan was administered daily by oral gavage to rats for up to 94 weeks and mice for up to 104 weeks. Evidence of carcinogenic potential of tegoprazan was identified in rats only and was limited to benign and/or malignant neuroendocrine cell tumors at exposures >7-fold of the recommended human dose. Glandular stomach findings were considered secondary to the expected pharmacology of tegoprazan, characterized by their location in the fundic and body regions of the stomach. Overall, tegoprazan induced gastric enterochromaffin-like (ECL) cell tumors in SD rats, but did not produce any treatment-related statistically significant increase in the incidence of neoplasms relevant to humans when administered to SD rats and CD-1 mice by gavage at doses up to 300 and 150 mg/kg/day, respectively. Gastric ECL cell tumors are thought to be induced by the exaggerated indirect pharmacological effect of tegoprazan, similar to that reported for proton pump inhibitors (PPIs) and other P-CABs.
Topics: Rats; Mice; Humans; Animals; Rats, Sprague-Dawley; Mice, Inbred ICR; Imidazoles; Stomach Neoplasms; Carcinogens
PubMed: 37295487
DOI: 10.1016/j.yrtph.2023.105424 -
Annals of Medicine and Surgery (2012) May 2023Bronchial carcinoid tumours are rare, slow-growing, malignant, Low-grade neuroendocrine tumours that arise from Enterochromaffin (Kulchitsky) cells and are usually...
UNLABELLED
Bronchial carcinoid tumours are rare, slow-growing, malignant, Low-grade neuroendocrine tumours that arise from Enterochromaffin (Kulchitsky) cells and are usually detected typically as indolent and solitary tumours. Approximately 2% of all lung tumours are bronchial carcinoid tumours.
CASE PRESENTATION
The authors report a case of 55-years-old man who presented with a history of cough for 1 month and was initially diagnosed with a case of COVID-19. Then he was treated as a case of pneumonia as seen on high-resolution computed tomography. Later, contrast-enhanced computed tomography and bronchoscopy-guided biopsy were done which revealed a right lower lobe neuroendocrine tumour (carcinoid), which was successfully resected.
CLINICAL DISCUSSION
The majority of typical carcinoids are located in the central airways leading to bronchial obstruction with recurrent pneumonia, chest pain, and wheezing. During the COVID-19 pandemic, lung cancer patients were at higher risk of being affected by COVID-19. This study emphasizes that early identification and differential diagnosis are extremely difficult in the absence of comprehensive study and workup as the clinical and imaging findings of COVID-19 may resemble lung cancer. Although hilar and mediastinal lymph nodes are the most common metastatic sites for typical carcinoids, most lymphadenopathies are caused by a reactive inflammatory reaction.
CONCLUSION
Bronchial carcinoids are uncommon, malignant neuroendocrine tumours for which the only curative management is complete surgical resection. With full resection, the result of typical carcinoids with lymph node metastases is favourable.
PubMed: 37229025
DOI: 10.1097/MS9.0000000000000653 -
Experimental and Therapeutic Medicine Jun 2023Neuroendocrine neoplasms (NENs) are a heterogenous group of tumors, arising from enterochromaffin cells, with different biological and clinical characteristics....
Neuroendocrine neoplasms (NENs) are a heterogenous group of tumors, arising from enterochromaffin cells, with different biological and clinical characteristics. Well-differentiated Grade 1 (G1) small intestinal NENs are often characterized by a slow progression rate and a good prognosis. Peritoneal carcinomatosis of a G1 digestive NEN is not a very common finding, and thus there is little published evidence regarding its progression and management. The complex, multistage interplay between the peritoneum and the metastasizing neuroendocrine cells is not well understood, and a reliable predictive tool to identify these patients earlier in their disease course is lacking. The present study describes the case of a 68-year-old woman presenting with an oligosymptomatic, stage IV, small intestinal G1 NEN (pTxpN1pM1) with synchronous liver metastases, multifocal mesenteric tumor deposits and a low Ki67 labeling index (1%). Over a period of 15 months, the patient developed rapidly progressive peritoneal metastatic disease with repetitive self-limiting obstructive symptoms and eventually succumbed to her illness. The present case report discusses the potential relationship between low-grade NEN, location of the primary tumor and the metastatic site, and also speculates on the role of the underlying subcellular mechanisms, specific micro-environment, spreading modalities and therapeutic strategy.
PubMed: 37206560
DOI: 10.3892/etm.2023.11982 -
Nature Cell Biology Jun 2023Insulin-producing β cells created from human pluripotent stem cells have potential as a therapy for insulin-dependent diabetes, but human pluripotent stem cell-derived...
Insulin-producing β cells created from human pluripotent stem cells have potential as a therapy for insulin-dependent diabetes, but human pluripotent stem cell-derived islets (SC-islets) still differ from their in vivo counterparts. To better understand the state of cell types within SC-islets and identify lineage specification deficiencies, we used single-nucleus multi-omic sequencing to analyse chromatin accessibility and transcriptional profiles of SC-islets and primary human islets. Here we provide an analysis that enabled the derivation of gene lists and activity for identifying each SC-islet cell type compared with primary islets. Within SC-islets, we found that the difference between β cells and awry enterochromaffin-like cells is a gradient of cell states rather than a stark difference in identity. Furthermore, transplantation of SC-islets in vivo improved cellular identities overtime, while long-term in vitro culture did not. Collectively, our results highlight the importance of chromatin and transcriptional landscapes during islet cell specification and maturation.
Topics: Humans; Multiomics; Cell Differentiation; Islets of Langerhans; Pluripotent Stem Cells; Chromatin; Insulins
PubMed: 37188763
DOI: 10.1038/s41556-023-01150-8 -
Gastroenterology Oct 2023
Topics: Humans; Enterochromaffin Cells; Duodenum; Serotonin
PubMed: 37178735
DOI: 10.1053/j.gastro.2023.05.008 -
Journal of Pharmacological Sciences Jun 2023We aimed to clarify the effect of nafamostat mesilate (nafamostat) on intestinal mucositis as well as the potentiation of intestinal 5-hydroxytryptamine (5-HT) dynamics...
We aimed to clarify the effect of nafamostat mesilate (nafamostat) on intestinal mucositis as well as the potentiation of intestinal 5-hydroxytryptamine (5-HT) dynamics induced by methotrexate, an anti-cancer drug, in rats. Rats received intraperitoneal methotrexate at 12.5 mg/kg/day for 4 days. In addition, 1, 3, or 10 mg/kg/day of nafamostat was given subcutaneously for 4 days. Ninety-six hours after the first administration of methotrexate, jejunal tissues were collected for analysis. The results showed that 1 mg/kg, but not 3 or 10 mg/kg, of nafamostat significantly ameliorated the methotrexate-induced body weight loss. Moreover, 1 mg/kg of nafamostat significantly improved methotrexate-induced mucositis, including villus atrophy. Nafamostat (1 mg/kg) significantly inhibited the methotrexate-induced mRNA expression of pro-inflammatory cytokines and cyclooxygenase-2, as well as methotrexate-induced 5-HT content and tryptophan hydroxylase (TPH) activity. In addition, it tended to inhibit the number of anti-TPH antibody-positive cells and significantly inhibited the number of anti-substance P antibody-positive cells. These findings suggest that low-dose nafamostat ameliorates tissue injury and 5-HT and substance P synthesis in methotrexate-induced mucositis. Nafamostat may be a novel therapeutic strategy for the prevention and treatment of mucositis as well as 5-HT- and/or substance P-related adverse effects in cancer chemotherapy.
Topics: Rats; Animals; Methotrexate; Serotonin; Mucositis; Intestines; Guanidines
PubMed: 37169484
DOI: 10.1016/j.jphs.2023.03.005 -
Journal of Diabetes Investigation Jul 2023A deficit of β-cells is a salient feature in both type 1 and type 2 diabetes mellitus. Due to the absolute lack of supplying β-cells for organ or cell...
A deficit of β-cells is a salient feature in both type 1 and type 2 diabetes mellitus. Due to the absolute lack of supplying β-cells for organ or cell transplantation, there is an urgent need to explore the efficient method to generate insulin-producing cells. Cell conversion of intestinal cryptic epithelial cells to insulin-producing β-like cells is a novel and promising therapeutic target. Activation of β-cell differentiation factors or modulation of terminally differentiated factors with forkhead homeobox O1 effectively induced such conversion, and suppressed hyperglycemia in streptozotocin-induced and non-obese diabetic (NOD) mice. Segi's cap, which was discovered >80 years ago, is composed of an aggregation of primitive granulated enteroendocrine cells, enterochromaffin cells, Paneth cells and goblet cells in the intestinal villi, and is only detected at the fetal stage. Its role has long been unknown, but the present study disclosed that it likely provides an underpin of newly generated β-like cells.
Topics: Animals; Mice; Diabetes Mellitus, Type 2; Mice, Inbred NOD; Intestinal Mucosa; Duodenum; Cell Differentiation; Insulins; Insulin; Insulin-Secreting Cells
PubMed: 37132053
DOI: 10.1111/jdi.14025