Expression of MUC2 and MUC3 mRNA in human normal, malignant, and inflammatory intestinal tissues.

MUC2 and MUC3 are prominent mucin genes expressed in the human intestine. Using in situ hybridization with RNA probes, we examined the cellular distribution of MUC2 and MUC3 mRNA in normal, malignant, and inflammatory human intestinal tissues. In normal small intestine and colon, MUC2 mRNA was expressed exclusively in goblet cells and occurred throughout the entire height of the mucosa. MUC3 mRNA was expressed by goblet and columnar cells but was restricted to the villous compartment of the small intestine and the surface epithelium of the colon. Expression of MUC2 and MUC3 mRNA were both markedly decreased in poorly, moderately, and well-differentiated colon cancers but were preserved in mucinous colon cancers. In ulcerative colitis and Crohn's colitis tissues, MUC2 and MUC3 mRNA expression displayed a normal pattern regardless of whether the mucosa manifested active or quiescent inflammation. These findings indicate that MUC2 is goblet cell-specific, whereas MUC3 is related to maturation of intestinal epithelial cells. In colon cancers, the genetic regulation of MUC2 and MUC3 is different depending on the histological type of tumor. The constitutive expression of MUC2 and MUC3 mRNA in inflammatory bowel diseases suggests that these genes may be necessary for maintenance of normal epithelial cell function during inflammation.

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Modeling Intestinal Stem Cell Function with Organoids

International Journal of Molecular Sciences ◽

10.3390/ijms222010912 ◽

2021 ◽

Vol 22 (20) ◽

pp. 10912

Author(s):

Toshio Takahashi ◽

Kazuto Fujishima ◽

Mineko Kengaku

Keyword(s):

Small Intestine ◽

Cell Function ◽

Cell Types ◽

Great Promise ◽

Epithelial Tissue ◽

Intestinal Epithelial ◽

Cholinergic Signaling ◽

New Treatments ◽

Efficient Expansion

Intestinal epithelial cells (IECs) are crucial for the digestive process and nutrient absorption. The intestinal epithelium is composed of the different cell types of the small intestine (mainly, enterocytes, goblet cells, Paneth cells, enteroendocrine cells, and tuft cells). The small intestine is characterized by the presence of crypt-villus units that are in a state of homeostatic cell turnover. Organoid technology enables an efficient expansion of intestinal epithelial tissue in vitro. Thus, organoids hold great promise for use in medical research and in the development of new treatments. At present, the cholinergic system involved in IECs and intestinal stem cells (ISCs) are attracting a great deal of attention. Thus, understanding the biological processes triggered by epithelial cholinergic activation by acetylcholine (ACh), which is produced and released from neuronal and/or non-neuronal tissue, is of key importance. Cholinergic signaling via ACh receptors plays a pivotal role in IEC growth and differentiation. Here, we discuss current views on neuronal innervation and non-neuronal control of the small intestinal crypts and their impact on ISC proliferation, differentiation, and maintenance. Since technology using intestinal organoid culture systems is advancing, we also outline an organoid-based organ replacement approach for intestinal diseases.

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An INF-STAT Axis Augments Tissue Damage and Inflammation in a Mouse Model of Crohn's Disease

Frontiers in Medicine ◽

10.3389/fmed.2021.644244 ◽

2021 ◽

Vol 8 ◽

Author(s):

Iris Stolzer ◽

Anja Dressel ◽

Mircea T. Chiriac ◽

Markus F. Neurath ◽

Claudia Günther

Keyword(s):

Cell Death ◽

Small Intestine ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Cell Function ◽

Paneth Cell ◽

Intestinal Epithelial ◽

Jak Inhibitors ◽

Inflammatory Bowel ◽

Epithelial Cell Death

Blocking interferon-function by therapeutic intervention of the JAK-STAT-axis is a novel promising treatment option for inflammatory bowel disease (IBD). Although JAK inhibitors have proven efficacy in patients with active ulcerative colitis (UC), they failed to induce clinical remission in patients with Crohn's disease (CD). This finding strongly implicates a differential contribution of JAK signaling in both entities. Here, we dissected the contribution of different STAT members downstream of JAK to inflammation and barrier dysfunction in a mouse model of Crohn's disease like ileitis and colitis (Casp8ΔIEC mice). Deletion of STAT1 in Casp8ΔIEC mice was associated with reduced cell death and a partial rescue of Paneth cell function in the small intestine. Likewise, organoids derived from the small intestine of these mice were less sensitive to cell death triggered by IBD-key cytokines such as TNFα or IFNs. Further functional in vitro and in vivo analyses revealed the impairment of MLKL-mediated necrosis as a result of deficient STAT1 function, which was in turn associated with improved cell survival. However, a decrease in inflammatory cell death was still associated with mild inflammation in the small intestine. The impact of STAT1 signaling on gastrointestinal inflammation dependent on the localization of inflammation, as STAT1 is essential for intestinal epithelial cell death regulation in the small intestine, whereas it is not the key factor for intestinal epithelial cell death in the context of colitis. Of note, additional deletion of STAT2 was not sufficient to restore Paneth cell function but strongly ameliorated ileitis. In summary, we provide here compelling molecular evidence that STAT1 and STAT2, both contribute to intestinal homeostasis, but have non-redundant functions. Our results further demonstrate that STATs individually affect the distinct pathophysiology of inflammation in the ileum and colon, respectively, which might explain the diverse outcome of JAK inhibitors on inflammatory bowel diseases.

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Crohn's disease-derived monocytes fail to induce Paneth cell defensins

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1510084112 ◽

2015 ◽

Vol 112 (45) ◽

pp. 14000-14005 ◽

Cited By ~ 34

Author(s):

Lioba F. Courth ◽

Maureen J. Ostaff ◽

Daniela Mailänder-Sánchez ◽

Nisar P. Malek ◽

Eduard F. Stange ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Mononuclear Cells ◽

Cell Function ◽

Paneth Cell ◽

Constitutive Expression ◽

Paneth Cells ◽

Intestinal Epithelial ◽

Peripheral Blood Mononuclear ◽

Wnt Ligands

Crohn’s disease (CD) is associated with a multitude of genetic defects, many of which likely affect Paneth cell function. Paneth cells reside in the small intestine and produce antimicrobial peptides essential for the host barrier, principally human α-defensin 5 (HD5) and HD6. Patients with CD of the ileum are characterized by reduced constitutive expression of these peptides and, accordingly, compromised antimicrobial barrier function. Here, we present a previously unidentified regulatory mechanism of Paneth cell defensins. Using cultures of human ileal tissue, we showed that the secretome of peripheral blood mononuclear cells (PBMCs) from healthy controls restored the attenuated Paneth cell α-defensin expression characteristic of patients with ileal CD. Analysis of the Wnt pathway in both cultured biopsies and intestinal epithelial cells implicated Wnt ligands driving the PBMC effect, whereas various tested cytokines were ineffective. We further detected another defect in patients with ileal CD, because the PBMC secretomes derived from patients with CD were unable to restore the reduced HD5/HD6 expression. Accordingly, analysis of PBMC subtypes showed that monocytes of patients with CD express significantly lower levels of canonical Wnt ligands, including Wnt3, Wnt3a, Wnt1, and wntless Wnt ligand secretion mediator (Evi/Wls). These studies reveal an important cross-talk between bone marrow-derived cells and epithelial secretory Paneth cells. Defective Paneth cell-mediated innate immunity due to inadequate Wnt ligand stimulation by monocytes provides an additional mechanism in CD. Because defects of Paneth cell function stemming from various etiologies are overcome by Wnt ligands, this mechanism is a potential therapeutic target for this disease.

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miR-802 regulates Paneth cell function and enterocyte differentiation in the mouse small intestine

Nature Communications ◽

10.1038/s41467-021-23298-3 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Algera Goga ◽

Büsra Yagabasan ◽

Karolin Herrmanns ◽

Svenja Godbersen ◽

Pamuditha N. Silva ◽

...

Keyword(s):

Small Intestine ◽

Epithelial Cell ◽

Intestinal Epithelium ◽

Cell Function ◽

Paneth Cell ◽

Cell Types ◽

Intestinal Epithelial ◽

Genetic Ablation ◽

Epithelial Homeostasis ◽

Enterocyte Differentiation

AbstractThe intestinal epithelium is a complex structure that integrates digestive, immunological, neuroendocrine, and regenerative functions. Epithelial homeostasis is maintained by a coordinated cross-talk of different epithelial cell types. Loss of integrity of the intestinal epithelium plays a key role in inflammatory diseases and gastrointestinal infection. Here we show that the intestine-enriched miR-802 is a central regulator of intestinal epithelial cell proliferation, Paneth cell function, and enterocyte differentiation. Genetic ablation of mir-802 in the small intestine of mice leads to decreased glucose uptake, impaired enterocyte differentiation, increased Paneth cell function and intestinal epithelial proliferation. These effects are mediated in part through derepression of the miR-802 target Tmed9, a modulator of Wnt and lysozyme/defensin secretion in Paneth cells, and the downstream Wnt signaling components Fzd5 and Tcf4. Mutant Tmed9 mice harboring mutations in miR-802 binding sites partially recapitulate the augmented Paneth cell function of mice lacking miR-802. Our study demonstrates a broad miR-802 network that is important for the integration of signaling pathways of different cell types controlling epithelial homeostasis in the small intestine.

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The protease phenotype and crystalline nature of the granules of intraepithelial mast cells in Trichinella spiralis-infected mice

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100140464 ◽

1995 ◽

Vol 53 ◽

pp. 818-819

Author(s):

D.S. Friend ◽

N. Ghildyal ◽

M.F. Gurish ◽

K.F. Austen ◽

R.L. Stevens

Keyword(s):

Small Intestine ◽

Mast Cells ◽

Epithelial Cells ◽

Lamina Propria ◽

Trichinella Spiralis ◽

Intestinal Epithelial ◽

Carboxypeptidase A ◽

C3h Mice ◽

Granule Morphology ◽

Crystalline Nature

Trichinella spiralis induces a profound mastocytosis and eosinophilia in the small intestine of the infected mouse. Mouse mast cells (MC) store in their granules various combinations of at least five chymotryptic chymases [designated mouse MC protease (mMCP) 1 to 5], two tryptic proteases designated mMCP-6 and mMCP-7 and an exopeptidase, carboxypeptidase A (mMC-CPA). Using antipeptide, protease -specific antibodies to these MC granule proteases, immunohistochemistry was done to determine the distribution, number and protease phenotype of the MCs in the small intestine and spleen 10 to >60 days after Trichinella infection of BALB/c and C3H mice. TEM was performed to evaluate the granule morphology of the MCs between intestinal epithelial cells and in the lamina propria (mucosal MCs) and in the submucosa, muscle and serosa of the intestine (submucosal MCs).As noted in the table below, the number of submucosal MCs remained constant throughout the study. In contrast, on day 14, the number of MCs in the mucosa increased ~25 fold. Increased numbers of MCs were observed between epithelial cells in the mucosal crypts, in the lamina propria and to a lesser extent, between epithelial cells of the intestinal villi.

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Protective Role of Natural and Semi-Synthetic Tocopherols on TNFα-Induced ROS Production and ICAM-1 and Cl-2 Expression in HT29 Intestinal Epithelial Cells

Antioxidants ◽

10.3390/antiox10020160 ◽

2021 ◽

Vol 10 (2) ◽

pp. 160

Author(s):

Vladana Domazetovic ◽

Irene Falsetti ◽

Caterina Viglianisi ◽

Kristian Vasa ◽

Cinzia Aurilia ◽

...

Keyword(s):

Oxidative Stress ◽

Antioxidant Properties ◽

Intestinal Barrier ◽

Protective Role ◽

Intercellular Adhesion Molecule ◽

Intestinal Epithelial ◽

Intercellular Adhesion Molecule 1 ◽

Beneficial Effects ◽

Bowel Diseases

Vitamin E, a fat-soluble compound, possesses both antioxidant and non-antioxidant properties. In this study we evaluated, in intestinal HT29 cells, the role of natural tocopherols, α-Toc and δ-Toc, and two semi-synthetic derivatives, namely bis-δ-Toc sulfide (δ-Toc)2S and bis-δ-Toc disulfide (δ-Toc)2S2, on TNFα-induced oxidative stress, and intercellular adhesion molecule-1 (ICAM-1) and claudin-2 (Cl-2) expression. The role of tocopherols was compared to that of N-acetylcysteine (NAC), an antioxidant precursor of glutathione synthesis. The results show that all tocopherol containing derivatives used, prevented TNFα-induced oxidative stress and the increase of ICAM-1 and Cl-2 expression, and that (δ-Toc)2S and (δ-Toc)2S2 are more effective than δ-Toc and α-Toc. The beneficial effects demonstrated were due to tocopherol antioxidant properties, but suppression of TNFα-induced Cl-2 expression seems not only to be related with antioxidant ability. Indeed, while ICAM-1 expression is strongly related to the intracellular redox state, Cl-2 expression is TNFα-up-regulated by both redox and non-redox dependent mechanisms. Since ICAM-1 and Cl-2 increase intestinal bowel diseases, and cause excessive recruitment of immune cells and alteration of the intestinal barrier, natural and, above all, semi-synthetic tocopherols may have a potential role as a therapeutic support against intestinal chronic inflammation, in which TNFα represents an important proinflammatory mediator.

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Tu1198 Intestinal Epithelial Cell Extrusion and Microbial Virulence Are Altered in Pediatric Inflammatory Bowel Diseases

Gastroenterology ◽

10.1016/s0016-5085(14)62819-5 ◽

2014 ◽

Vol 146 (5) ◽

pp. S-781

Author(s):

Deenaz Zaidi ◽

Michael Bording-Jorgenson ◽

Hien Q. Huynh ◽

Yuefei Lou ◽

Julia J. Liu ◽

...

Keyword(s):

Epithelial Cell ◽

Inflammatory Bowel Diseases ◽

Intestinal Epithelial Cell ◽

Intestinal Epithelial ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Cell Extrusion

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P254 GALECTIN-2 AND GALECTIN-4 MODULATE INTESTINAL EPITHELIAL CELL FUNCTION AND INTESTINAL WOUND HEALING

Journal of Crohn s and Colitis Supplements ◽

10.1016/s1873-9954(08)70265-9 ◽

2008 ◽

Vol 2 (1) ◽

pp. 79

Author(s):

D. Paclik ◽

B. Wiedenmann ◽

A. Dignass ◽

A. Sturm

Keyword(s):

Wound Healing ◽

Epithelial Cell ◽

Intestinal Epithelial Cell ◽

Cell Function ◽

Intestinal Epithelial

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Is polyamine synthesis involved in the proliferative response of the intestinal epithelium to urogastrone-epidermal growth factor?

Clinical Science ◽

10.1042/cs0760595 ◽

1989 ◽

Vol 76 (6) ◽

pp. 595-598 ◽

Cited By ~ 11

Author(s):

R. A. Goodlad ◽

H. Gregory ◽

N. A. Wright

Keyword(s):

Cell Proliferation ◽

Small Intestine ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Proliferative Response ◽

Intestinal Cell ◽

Intestinal Epithelial ◽

Polyamine Synthesis ◽

Proliferative Effect ◽

Epidermal Growth

1. Intestinal epithelial cell proliferation was measured in rats maintained on total parenteral nutriton (TPN), in TPN rats given 300 μg of recombinant human epidermal growth factor (urogastrone-epidermal growth factor, URO-EGF) day−1 kg−1, and in further groups given URO-EGF and difluoromethylornithine (DFMO), an inhibitor of the enzyme ornithine decarboxylase (ODC). 2. URO-EGF significantly increased intestinal cell proliferation throughout the gastrointestinal tract. The proliferative response of the colon was particularly pronounced. 3. DFMO reduced the proliferative effect of urogastrone in the stomach and small intestine. DFMO also reduced URO-EGF-stimulated intestinal cell proliferation in the colon, but to a lesser extent. 4. It is concluded that ODC is essential for effecting the proliferative response of the stomach and small intestine to URO-EGF, but this role may be less important in the colon.

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