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1
Darmoul, D., D. Brown, M. E. Selsted, and A. J. Ouellette. "Cryptdin gene expression in developing mouse small intestine." American Journal of Physiology-Gastrointestinal and Liver Physiology 272, no. 1 (January 1, 1997): G197—G206. http://dx.doi.org/10.1152/ajpgi.1997.272.1.g197.
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In rodents, the four intestinal epithelial cell lineages differentiate and become morphologically distinct during the first 2-3 postnatal wk. In studies reported here, reverse transcriptase-polymerase chain reaction (RT-PCR)-based assays detected Paneth cell defensin mRNAs in intestinal RNA from 1-day-old (P1) mice before crypt formation and maturation of the epithelium. Analysis of these defensin-coding RT-PCR products from P1 mice showed that 69% of clones sequenced coded for cryptdin-6, suggesting that it is the most abundant enteric defensin mRNA in the newborn. Paneth cell mRNAs, including cryptdins-4 and -5, lysozyme, matrilysin, and defensin-related sequences, also were detected in RNA from P1 mouse intestine. Unlike adult mice, where only Paneth cells are immunopositive for cryptdin, cryptdin-containing cells were distributed throughout the newborn intestinal epithelium and not in association with rudimentary crypts. Cryptdin immunoreactivity in the P1 mouse intestine was specific for intracellular granule contents, and immunofluorescent detection of cryptdins on mucosal surfaces suggested that the peptides are released into the intestinal lumen in P1 mice Defensin secretion may contribute to innate immunity of the neonatal intestine before the presence of distinguishable Paneth cells.
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Schjoldager, Katrine T. B. G., Henrik R. Maltesen, Sophie Balmer, Leif R. Lund, Mogens H. Claesson, Hans Sjöström, Jesper T. Troelsen, and Jørgen Olsen. "Cellular cross talk in the small intestinal mucosa: postnatal lymphocytic immigration elicits a specific epithelial transcriptional response." American Journal of Physiology-Gastrointestinal and Liver Physiology 294, no. 6 (June 2008): G1335—G1343. http://dx.doi.org/10.1152/ajpgi.00265.2007.
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During the early postnatal period lymphocytes migrate into the mouse small intestine. Migrating infiltrative lymphocytes have the potential to affect the epithelial cells via secreted cytokines. Such cross talk can result in the elicitation of an epithelial transcriptional response. Knowledge about such physiological cross talk between the immune system and the epithelium in the postnatal small intestinal mucosa is lacking. We have investigated the transcriptome changes occurring in the postnatal mouse small intestine using DNA microarray technology, immunocytochemistry, and quantitative real-time RT-PCR analysis. The DNA microarray data were analyzed bioinformatically by using a combination of projections to latent structures analysis and functional annotation analysis. The results show that infiltrating lymphocytes appear in the mouse small intestine in the late postweaning period and give rise to distinct changes in the epithelial transcriptome. Of particular interest is the expression of three genes encoding a mucin ( Muc4), a mucinlike protein ( 16000D21Rik), and ATP citrate lyase (Acly). All three genes were shown to be expressed by the epithelium and to be upregulated in response to lymphocytic migration into the small intestinal mucosa.
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Hofmann, Felix, Torsten Thalheim, Karen Rother, Marianne Quaas, Christiane Kerner, Jens Przybilla, Gabriela Aust, and Joerg Galle. "How to Obtain a Mega-Intestine with Normal Morphology: In Silico Modelling of Postnatal Intestinal Growth in a Cd97-Transgenic Mouse." International Journal of Molecular Sciences 22, no. 14 (July 8, 2021): 7345. http://dx.doi.org/10.3390/ijms22147345.
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Intestinal cylindrical growth peaks in mice a few weeks after birth, simultaneously with crypt fission activity. It nearly stops after weaning and cannot be reactivated later. Transgenic mice expressing Cd97/Adgre5 in the intestinal epithelium develop a mega-intestine with normal microscopic morphology in adult mice. Here, we demonstrate premature intestinal differentiation in Cd97/Adgre5 transgenic mice at both the cellular and molecular levels until postnatal day 14. Subsequently, the growth of the intestinal epithelium becomes activated and its maturation suppressed. These changes are paralleled by postnatal regulation of growth factors and by an increased expression of secretory cell markers, suggesting growth activation of non-epithelial tissue layers as the origin of enforced tissue growth. To understand postnatal intestinal growth mechanistically, we study epithelial fate decisions during this period with the use of a 3D individual cell-based computer model. In the model, the expansion of the intestinal stem cell (SC) population, a prerequisite for crypt fission, is largely independent of the tissue growth rate and is therefore not spontaneously adaptive. Accordingly, the model suggests that, besides the growth activation of non-epithelial tissue layers, the formation of a mega-intestine requires a released growth control in the epithelium, enabling accelerated SC expansion. The similar intestinal morphology in Cd97/Adgre5 transgenic and wild type mice indicates a synchronization of tissue growth and SC expansion, likely by a crypt density-controlled contact inhibition of growth of intestinal SC proliferation. The formation of a mega-intestine with normal microscopic morphology turns out to originate in changes of autonomous and conditional specification of the intestinal cell fate induced by the activation of Cd97/Adgre5.
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Chen, Chin, Rixun Fang, Corrine Davis, Charalambos Maravelias, and Eric Sibley. "Pdx1 inactivation restricted to the intestinal epithelium in mice alters duodenal gene expression in enterocytes and enteroendocrine cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 297, no. 6 (December 2009): G1126—G1137. http://dx.doi.org/10.1152/ajpgi.90586.2008.
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Null mutant mice lacking the transcription factor pancreatic and duodenal homeobox 1 (Pdx1) are apancreatic and survive only a few days after birth. The role of Pdx1 in regulating intestinal gene expression has therefore yet to be determined in viable mice with normal pancreatic development. We hypothesized that conditional inactivation of Pdx1 restricted to the intestinal epithelium would alter intestinal gene expression and cell differentiation. Pdx1 flox/flox; VilCre mice with intestine-specific Pdx1 inactivation were generated by crossing a transgenic mouse strain expressing Cre recombinase, driven by a mouse villin 1 gene promoter fragment, with a mutant mouse strain homozygous for loxP site-flanked Pdx1. Pdx1 protein is undetectable in all epithelial cells in the intestinal epithelium of Pdx1 flox/flox; VilCre mice. Goblet cell number and mRNA abundance for mucin 3 and mucin 13 genes in the proximal small intestine are comparable between Pdx1 flox/flox; VilCre and control mice. Similarly, Paneth cell number and expression of Paneth cell-related genes Defa1, Defcr-rs1, and Mmp7 in the proximal small intestine remain statistically unchanged by Pdx1 inactivation. Although the number of enteroendocrine cells expressing chromogranin A/B, gastric inhibitory polypeptide (Gip), or somatostatin (Sst) is unaffected in the Pdx1 flox/flox; VilCre mice, mRNA abundance for Gip and Sst is significantly reduced in the proximal small intestine. Conditional Pdx1 inactivation attenuates intestinal alkaline phosphatase (IAP) activity in the duodenal epithelium, consistent with an average 91% decrease in expression of the mouse enterocyte IAP gene, alkaline phosphatase 3 (a novel Pdx1 target candidate), in the proximal small intestine following Pdx1 inactivation. We conclude that Pdx1 is necessary for patterning appropriate gene expression in enterocytes and enteroendocrine cells of the proximal small intestine.
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Maharshak, Nitsan, Eun Young Huh, Chorlada Paiboonrungruang, Michael Shanahan, Lance Thurlow, Jeremy Herzog, Zorka Djukic, et al. "Enterococcus faecalis Gelatinase Mediates Intestinal Permeability via Protease-Activated Receptor 2." Infection and Immunity 83, no. 7 (April 27, 2015): 2762–70. http://dx.doi.org/10.1128/iai.00425-15.
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Microbial protease-mediated disruption of the intestinal epithelium is a potential mechanism whereby a dysbiotic enteric microbiota can lead to disease. This mechanism was investigated using the colitogenic, protease-secreting enteric microbeEnterococcus faecalis. Caco-2 and T-84 epithelial cell monolayers and the mouse colonic epithelium were exposed to concentrated conditioned media (CCM) fromE. faecalisV583 andE. faecalislacking the gelatinase gene (gelE). The flux of fluorescein isothiocyanate (FITC)-labeled dextran across monolayers or the mouse epithelium following exposure to CCM from parental or mutantE. faecalisstrains indicated paracellular permeability. A protease-activated receptor 2 (PAR2) antagonist and PAR2-deficient (PAR2−/−) mice were used to investigate the role of this receptor inE. faecalis-induced permeability. Gelatinase (GelE) purified fromE. faecalisV583 was used to confirm the ability of this protease to induce epithelial cell permeability and activate PAR2. The protease-mediated permeability of colonic epithelia from wild-type (WT) and PAR2−/−mice by fecal supernatants from ulcerative colitis patients was assessed. SecretedE. faecalisproteins induced permeability in epithelial cell monolayers, which was reduced in the absence ofgelEor by blocking PAR2 activity. SecretedE. faecalisproteins induced permeability in the colonic epithelia of WT mice that was absent in tissues from PAR2−/−mice. Purified GelE confirmed the ability of this protease to induce epithelial cell permeability via PAR2 activation. Fecal supernatants from ulcerative colitis patients induced permeability in the colonic epithelia of WT mice that was reduced in tissues from PAR2−/−mice. Our investigations demonstrate that GelE fromE. faecaliscan regulate enteric epithelial permeability via PAR2.
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Babeu, Jean-Philippe, Mathieu Darsigny, Carine R. Lussier, and François Boudreau. "Hepatocyte nuclear factor 4α contributes to an intestinal epithelial phenotype in vitro and plays a partial role in mouse intestinal epithelium differentiation." American Journal of Physiology-Gastrointestinal and Liver Physiology 297, no. 1 (July 2009): G124—G134. http://dx.doi.org/10.1152/ajpgi.90690.2008.
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Hepatocyte nuclear factor 4α (HNF4α) is a regulator of hepatocyte and pancreatic transcription. Hnf4α deletion in the mouse is embryonically lethal with severe defects in visceral endoderm formation. It has been concluded in the past that the role of Hnf4α in the developing colon was much less important than in the liver. However, the precise role of Hnf4α in the homeostasis of the small intestinal epithelium remains unclear. Our aim was to evaluate the potential of Hnf4α to support an intestinal epithelial phenotype. First, Hnf4α potential to dictate this phenotype was assessed in nonintestinal cell lines in vitro. Forced expression of Hnf4α in fibroblasts showed an induction of features normally restricted to epithelial cells. Combinatory expression of Hnf4α with specific transcriptional regulators of the intestine resulted in the induction of intestinal epithelial genes in this context. Second, the importance of Hnf4α in maintaining the homeostasis of the intestinal epithelium was investigated in mice. Mice conditionally deficient for intestinal Hnf4α developed normally throughout adulthood with an epithelium displaying normal morphological and functional structures with minor alterations. Subtle but statistical differences were observed at the proliferation and the cytodifferentiation levels. Hnf4α mutant mice displayed an increase in the number of goblet and enteroendocrine cells compared with controls. Given the fundamental role of this transcription factor in other tissues, these findings dispute the crucial role for this regulator in the maintenance of intestinal epithelial cell function at a period of time that follows cytodifferentiation but may suggest a functional role in instructing cells to become specific to the intestinal epithelium.
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Li, Yan, Yun-Yan Xiang, Wei-Yang Lu, Chuanyong Liu, and Jingxin Li. "A novel role of intestine epithelial GABAergic signaling in regulating intestinal fluid secretion." American Journal of Physiology-Gastrointestinal and Liver Physiology 303, no. 4 (August 15, 2012): G453—G460. http://dx.doi.org/10.1152/ajpgi.00497.2011.
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γ-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system, and it is produced via the enzymatic activity of glutamic acid decarboxylase (GAD). GABA generates fast biological signaling through type A receptors (GABAAR), an anionic channel. Intriguingly, GABA is found in the jejunum epithelium of rats. The present study intended to determine whether a functional GABA signaling system exists in the intestinal epithelium and if so whether the GABA signaling regulates intestinal epithelial functions. RT-PCR, Western blot, and immunohistochemical assays of small intestinal tissues of various species were performed to determine the expression of GABA-signaling proteins in intestinal epithelial cells. Perforated patch-clamp recording was used to measure GABA-induced transmembrane current in the small intestine epithelial cell line IEC-18. The fluid weight-to-intestine length ratio was measured in mice that were treated with GABAAR agonist and antagonist. The effect of GABAAR antagonist on allergic diarrhea was examined using a mouse model. GABA, GAD, and GABAAR subunits were identified in small intestine epithelial cells of mice, rats, pigs, and humans. GABAAR agonist induced an inward current and depolarized IEC-18. Both GABA and the GABAAR agonist muscimol increased intestinal fluid secretion of rats. The increased intestinal secretion was largely decreased by the GABAAR antagonist picrotoxin or gabazine, but not by tetrodotoxin. The expression levels of GABA-signaling proteins were increased in the intestinal epithelium of mice that were sensitized and challenged with ovalbumin (OVA). The OVA-treated mice exhibited diarrhea, which was alleviated by oral administration of gabazine or picrotoxin. An endogenous autocrine GABAergic signaling exists in the mammalian intestinal epithelium, which upregulates intestinal fluid secretion. The intestinal GABAergic signaling becomes intensified in allergic diarrhea, and inhibition of this GABA-signal system alleviates the allergic diarrhea.
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Gerbe, François, Johan H. van Es, Leila Makrini, Bénédicte Brulin, Georg Mellitzer, Sylvie Robine, Béatrice Romagnolo, et al. "Distinct ATOH1 and Neurog3 requirements define tuft cells as a new secretory cell type in the intestinal epithelium." Journal of Cell Biology 192, no. 5 (March 7, 2011): 767–80. http://dx.doi.org/10.1083/jcb.201010127.
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The unique morphology of tuft cells was first revealed by electron microscopy analyses in several endoderm-derived epithelia. Here, we explore the relationship of these cells with the other cell types of the intestinal epithelium and describe the first marker signature allowing their unambiguous identification. We demonstrate that although mature tuft cells express DCLK1, a putative marker of quiescent stem cells, they are post-mitotic, short lived, derive from Lgr5-expressing epithelial stem cells, and are found in mouse and human tumors. We show that whereas the ATOH1/MATH1 transcription factor is essential for their differentiation, Neurog3, SOX9, GFI1, and SPDEF are dispensable, which distinguishes these cells from enteroendocrine, Paneth, and goblet cells, and raises from three to four the number of secretory cell types in the intestinal epithelium. Moreover, we show that tuft cells are the main source of endogenous intestinal opioids and are the only epithelial cells that express cyclooxygenase enzymes, suggesting important roles for these cells in the intestinal epithelium physiopathology.
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Blache, Philippe, Marc van de Wetering, Isabelle Duluc, Claire Domon, Philippe Berta, Jean-Noël Freund, Hans Clevers, and Philippe Jay. "SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 genes." Journal of Cell Biology 166, no. 1 (July 5, 2004): 37–47. http://dx.doi.org/10.1083/jcb.200311021.
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TCF and SOX proteins belong to the high mobility group box transcription factor family. Whereas TCFs, the transcriptional effectors of the Wnt pathway, have been widely implicated in the development, homeostasis and disease of the intestine epithelium, little is known about the function of the SOX proteins in this tissue. Here, we identified SOX9 in a SOX expression screening in the mouse fetal intestine. We report that the SOX9 protein is expressed in the intestinal epithelium in a pattern characteristic of Wnt targets. We provide in vitro and in vivo evidence that a bipartite β-catenin/TCF4 transcription factor, the effector of the Wnt signaling pathway, is required for SOX9 expression in epithelial cells. Finally, in colon epithelium-derived cells, SOX9 transcriptionally represses the CDX2 and MUC2 genes, normally expressed in the mature villus cells of the intestinal epithelium, and may therefore contribute to the Wnt-dependent maintenance of a progenitor cell phenotype.
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Hodges, Craig A., Brian R. Grady, Kirtishri Mishra, Calvin U. Cotton, and Mitchell L. Drumm. "Cystic fibrosis growth retardation is not correlated with loss of Cftr in the intestinal epithelium." American Journal of Physiology-Gastrointestinal and Liver Physiology 301, no. 3 (September 2011): G528—G536. http://dx.doi.org/10.1152/ajpgi.00052.2011.
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Maldigestion due to exocrine pancreatic insufficiency leads to intestinal malabsorption and consequent malnutrition, a mechanism proposed to cause growth retardation associated with cystic fibrosis (CF). However, although enzyme replacement therapy combined with increased caloric intake improves weight gain, the effect on stature is not significant, suggesting that growth retardation has a more complex etiology. Mouse models of CF support this, since these animals do not experience exocrine pancreatic insufficiency yet are growth impaired. Cftr absence from the intestinal epithelium has been suggested as a primary source of growth retardation in CF mice, a concept we directly tested by generating mouse models with Cftr selectively inactivated or restored in intestinal epithelium. The relationship between growth and functional characteristics of the intestines, including transepithelial electrophysiology, incidence of intestinal obstruction, and histopathology, were assessed. Absence of Cftr exclusively from intestinal epithelium resulted in loss of cAMP-stimulated short-circuit current, goblet cell hyperplasia, and occurrence of intestinal obstructions but only slight and transient impaired growth. In contrast, specifically restoring Cftr to the intestinal epithelium resulted in restoration of ion transport and completely protected against obstruction and histopathological anomalies, but growth was indistinguishable from CF mice. These results indicate that absence of Cftr in the intestinal epithelium is an important contributor to the intestinal obstruction phenotype in CF but does not correlate with the observed growth reduction in CF.
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Grant, Christa N., Salvador Garcia Mojica, Frederic G. Sala, J. Ryan Hill, Daniel E. Levin, Allison L. Speer, Erik R. Barthel, Hiroyuki Shimada, Nicholas C. Zachos, and Tracy C. Grikscheit. "Human and mouse tissue-engineered small intestine both demonstrate digestive and absorptive function." American Journal of Physiology-Gastrointestinal and Liver Physiology 308, no. 8 (April 15, 2015): G664—G677. http://dx.doi.org/10.1152/ajpgi.00111.2014.
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Short bowel syndrome (SBS) is a devastating condition in which insufficient small intestinal surface area results in malnutrition and dependence on intravenous parenteral nutrition. There is an increasing incidence of SBS, particularly in premature babies and newborns with congenital intestinal anomalies. Tissue-engineered small intestine (TESI) offers a therapeutic alternative to the current standard treatment, intestinal transplantation, and has the potential to solve its biggest challenges, namely donor shortage and life-long immunosuppression. We have previously demonstrated that TESI can be generated from mouse and human small intestine and histologically replicates key components of native intestine. We hypothesized that TESI also recapitulates native small intestine function. Organoid units were generated from mouse or human donor intestine and implanted into genetically identical or immunodeficient host mice. After 4 wk, TESI was harvested and either fixed and paraffin embedded or immediately subjected to assays to illustrate function. We demonstrated that both mouse and human tissue-engineered small intestine grew into an appropriately polarized sphere of intact epithelium facing a lumen, contiguous with supporting mesenchyme, muscle, and stem/progenitor cells. The epithelium demonstrated major ultrastructural components, including tight junctions and microvilli, transporters, and functional brush-border and digestive enzymes. This study demonstrates that tissue-engineered small intestine possesses a well-differentiated epithelium with intact ion transporters/channels, functional brush-border enzymes, and similar ultrastructural components to native tissue, including progenitor cells, whether derived from mouse or human cells.
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Takizawa, Satoshi, Tsuyoshi Uchide, Javier Adur, Takaharu Kozakai, Eiichi Kotake-Nara, Jiexia Quan, and Kaname Saida. "Differential expression of endothelin-2 along the mouse intestinal tract." Journal of Molecular Endocrinology 35, no. 2 (October 2005): 201–9. http://dx.doi.org/10.1677/jme.1.01787.
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Endothelin (ET)-2, an ET family peptide, is highly expressed in intestine. However, the specific distribution and function of ET-2 remain unknown. We elucidated the expression profile and localization of ET-2 in mouse gastrointestinal tract. Real-time PCR analysis revealed that ET-2 gene expression in the gastrointestinal tract of healthy animals was relatively high in the colon. Immunohistochemical analysis revealed ET-2-like immunoreactivity mainly in epithelial cells of the mucosa throughout the intestinal tract of healthy animals. Intracellularly, ET-2 was concentrated close to the basement membrane of intestinal epithelial cells. A weak ET-2-like immunoreactivity was also localized to some neurofibers and the myenteric plexus of the muscle layer, coexpressing with vasoactive intestinal peptide. ET-2-like immunoreactivity was also detected at Brunner’s glands of the duodenum and follicle-associated epithelium of Peyer’s patch. In contrast, ET-1-like immunoreactivity was uniformly distributed in epithelial cells. In dextran sulfate sodium (DSS)-induced colitis, colonic ET-2 was upregulated during the late stage of DSS treatment. These results suggest that in intestinal epithelial cells ET-2 could be secreted into the lamina propria and the dome region in Peyer’s patch, and that it might modulate immune cells in these sites for mucosal defense.
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Suh, Eunran, Zhengqi Wang, Gary P. Swain, Martin Tenniswood, and Peter G. Traber. "Clusterin gene transcription is activated by caudal-related homeobox genes in intestinal epithelium." American Journal of Physiology-Gastrointestinal and Liver Physiology 280, no. 1 (January 1, 2001): G149—G156. http://dx.doi.org/10.1152/ajpgi.2001.280.1.g149.
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Caudal-related homeobox (Cdx) proteins play an important role in development and differentiation of the intestinal epithelium. Using cDNA differential display, we identified clusterin as a prominently induced gene in a Cdx2-regulated cellular model of intestinal differentiation. Transfection experiments and DNA-protein interaction assays showed that clusterin is an immediate downstream target gene for Cdx proteins. The distribution of clusterin protein in the intestine was assessed during development and in the adult epithelium using immunohistochemistry. In the adult mouse epithelium, clusterin protein was localized in both crypt and villus compartments but not in interstitial cells of the intestinal mucosa. Together, these data suggest that clusterin is a direct target gene for Cdx homeobox proteins, and the pattern of clusterin protein expression suggests that it is associated with the differentiated state in the intestinal epithelium.
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Parmar, Naveen, Kyle Burrows, Pia M. Vornewald, Håvard T. Lindholm, Rosalie T. Zwiggelaar, Alberto Díez-Sánchez, Mara Martín-Alonso, et al. "Intestinal-epithelial LSD1 controls goblet cell maturation and effector responses required for gut immunity to bacterial and helminth infection." PLOS Pathogens 17, no. 3 (March 31, 2021): e1009476. http://dx.doi.org/10.1371/journal.ppat.1009476.
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Infectious and inflammatory diseases in the intestine remain a serious threat for patients world-wide. Reprogramming of the intestinal epithelium towards a protective effector state is important to manage inflammation and immunity and can be therapeutically targeted. The role of epigenetic regulatory enzymes within these processes is not yet defined. Here, we use a mouse model that has an intestinal-epithelial specific deletion of the histone demethylase Lsd1 (cKO mice), which maintains the epithelium in a fixed reparative state. Challenge of cKO mice with bacteria-induced colitis or a helminth infection model both resulted in increased pathogenesis. Mechanistically, we discovered that LSD1 is important for goblet cell maturation and goblet-cell effector molecules such as RELMß. We propose that this may be in part mediated by directly controlling genes that facilitate cytoskeletal organization, which is important in goblet cell biology. This study therefore identifies intestinal-epithelial epigenetic regulation by LSD1 as a critical element in host protection from infection.
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Wu, M., L. van Kaer, S. Itohara, and S. Tonegawa. "Highly restricted expression of the thymus leukemia antigens on intestinal epithelial cells." Journal of Experimental Medicine 174, no. 1 (July 1, 1991): 213–18. http://dx.doi.org/10.1084/jem.174.1.213.
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The TL region of the major histocompatibility complex of the mouse contains dozens of tandemly arranged class I genes, including those encoding the thymus leukemia (TL) antigens. TL antigens have been thought to be expressed only on the surface of some T lineage cells, namely immature thymocytes of some mouse strains (TL+ strains), some leukemia cells, and activated T cells. While the function of TL antigens is unknown, recent studies have implicated the products of at least some TL region class I genes as molecules that present antigens to gamma/delta T cells. Since some gamma/delta T cells are known to be specifically associated with certain epithelial tissues, we have investigated the expression of some TL region class I genes in a variety of epithelium-containing tissues. Our results show that the TL antigen gene of C57BL/6 mice, T3b, and the TL antigen genes of BALB/c mice, T3d (previously T3c) and T18d (previously T13c), are highly expressed in the epithelium of the small intestine. In the case of T3b, we further show, using a T3 product-specific antibody, that its product is expressed on the surface of the columnar epithelial cells. In addition, we demonstrated that two other TL region class I genes of C57BL/6 origin, T9b and T21b, are also expressed nearly exclusively in intestinal epithelial cells. These results are consistent with the hypothesis that the products of these TL region class I genes are recognized by gamma/delta T cell receptors of intestinal intraepithelial lymphocytes, a subset of gamma/delta T cells that is localized in the intestinal epithelium and has a restricted V gamma repertoire. Finally, our study indicates that the relative levels of expression of the two homologous TL antigen genes, T3d and T18d, differ widely between the thymus and the intestine.
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Savkovic, Suzana D., Jennilee Villanueva, Jerrold R. Turner, Kristina A. Matkowskyj, and Gail Hecht. "Mouse Model of Enteropathogenic Escherichia coli Infection." Infection and Immunity 73, no. 2 (February 2005): 1161–70. http://dx.doi.org/10.1128/iai.73.2.1161-1170.2005.
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ABSTRACT Enteropathogenic Escherichia coli (EPEC) is an important cause of diarrhea in humans. EPEC infection of cultured intestinal epithelial cells induces attaching and effacing (A/E) lesions, alters intestinal ion transport, increases paracellular permeability, and stimulates inflammation. The lack of a small-animal model has restricted in vivo studies examining EPEC-host interactions. The aim of this study was to characterize the C57BL/6J mouse as a model of EPEC infection. We have shown that EPEC can adhere to and colonize the intestinal epithelium of C57BL/6J mice. Animal weight and water intake were not altered during 10 days of EPEC infection. The proximal colon of infected mice contained semisolid stool, with stool pellets forming only in the distal colon. In contrast, the entire colon of control mice contained formed stool. Microvillous effacement and actin rearrangement, characteristic of A/E lesions, were seen in the intestine of infected mice but not control mice. Histological assessment revealed increased numbers of lamina propria neutrophils with occasional crypt abscesses, intraepithelial lymphocytes, and goblet cells in the intestine of EPEC-infected mice. Altogether, these data suggest that the C57BL/6J mouse is susceptible to infection by EPEC and will provide a suitable in vivo model for studying the consequences of EPEC infection.
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Ezzell, R. M., M. M. Chafel, and P. T. Matsudaira. "Differential localization of villin and fimbrin during development of the mouse visceral endoderm and intestinal epithelium." Development 106, no. 2 (June 1, 1989): 407–19. http://dx.doi.org/10.1242/dev.106.2.407.
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The apical surface of transporting epithelia is specially modified to absorb nutrients efficiently by amplifying its surface area as microvilli. Each microvillus is supported by an underlying core of bundled actin filaments. Villin and fimbrin are two actin-binding proteins that bundle actin filaments in the intestine and kidney brush border epithelium. To better understand their function in the assembly of the cytoskeleton during epithelial differentiation, we examined the pattern of villin and fimbrin expression in the developing mouse using immunofluorescence and immunoelectron microscopy. Villin is first detected at day 5 in the primitive endoderm of the postimplantation embryo and is later restricted to the visceral endoderm. By day 8.5, villin becomes redistributed to the apical surface in the visceral endoderm, appearing in the gut at day 10 and concentrating in the apical cytoplasm of the differentiating intestinal epithelium 2–3 days later. In contrast, fimbrin is found in the oocyte and in all tissues of the early embryo. In both the visceral endoderm and gut epithelium, fimbrin concentrates at the apical surface 2–3 days after villin; this redistribution occurs when the visceral endoderm microvilli first contain organized microfilament bundles and when microvilli first begin to appear in the gut. These results suggest a common mechanism of assembly of the absorptive surface of two different tissues in the embryo and identify villin as a useful marker for the visceral endoderm.
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Cheng, Zhuan-Fen, and Christine A. Cartwright. "Rack1 maintains intestinal homeostasis by protecting the integrity of the epithelial barrier." American Journal of Physiology-Gastrointestinal and Liver Physiology 314, no. 2 (February 1, 2018): G263—G274. http://dx.doi.org/10.1152/ajpgi.00241.2017.
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Previously, we generated mouse models of Rack1 deficiency to identify key functions for Rack1 in regulating growth of intestinal epithelia: suppressing crypt cell proliferation and regeneration, promoting differentiation and apoptosis, and repressing development of neoplasia. However, other than low body weight, we did not detect an overt phenotype in mice constitutively deleted of Rack1 in intestinal epithelia ( vil-Cre: Rack1fl/fl mice), presumably because Rack1 was deleted in <10% of the total surface area of the epithelia. To assess the effect of Rack1 loss throughout the entire intestinal epithelia, we generated another mouse model of Rack1 deficiency, vil-Cre-ERT2: Rack1fl/fl. Within 5–10 days of the initial tamoxifen treatment, the mice lost over 20% of their body weight, developed severe diarrhea that for some was bloody, became critically ill, and died, if not euthanized. Necropsies revealed mildly distended, fluid-, gas-, and sometimes blood-filled loops of small and large bowel, inguinal lymphadenopathy, and thrombocytosis. Rack1 was deleted in nearly 100% of the epithelia in both the small intestine and colon when assessed by immunofluorescent or immunoblot analyses. Rack1 expression in other tissues and organs was not different than in control mice, indicating tissue specificity of the recombination. Histopathology revealed a patchy, erosive, hemorrhagic, inflammatory enterocolitis with denuded, sloughed off surface epithelium, and crypt hyperplasia. These results suggest a protective function for Rack1 in maintaining the integrity of intestinal epithelia and for survival. NEW & NOTEWORTHY Our findings reveal a novel function for Rack1 in maintaining intestinal homeostasis by protecting the epithelial barrier. Rack1 loss results in a patchy, erosive, hemorrhagic, inflammatory enterocolitis, which resembles that of inflammatory bowel diseases (IBD) in humans. Understanding mechanisms that protect barrier function in normal intestine and how loss of that protection contributes to the pathogenesis of IBD could lead to improved therapies for these and other erosive diseases of the gastrointestinal tract.
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Stappenbeck, T. S., and J. I. Gordon. "Rac1 mutations produce aberrant epithelial differentiation in the developing and adult mouse small intestine." Development 127, no. 12 (June 15, 2000): 2629–42. http://dx.doi.org/10.1242/dev.127.12.2629.
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The mouse small intestinal epithelium undergoes continuous renewal throughout life. Previous studies suggest that differentiation of this epithelium is regulated by instructions that are received as cells migrate along crypt-villus units. The nature of the instructions and their intracellular processing remain largely undefined. In this report, we have used genetic mosaic analysis to examine the role of Rac1 GTPase-mediated signaling in controlling differentiation. A constitutively active mutation (Rac1Leu61) or a dominant negative mutation (Rac1Asn17) was expressed in the 129/Sv embryonic stem cell-derived component of the small intestine of C57Bl/6-ROSA26<->129/Sv mice. Rac1Leu61 induces precocious differentiation of members of the Paneth cell and enterocytic lineages in the proliferative compartment of the fetal gut, without suppressing cell division. Forced expression of the dominant negative mutation inhibits epithelial differentiation, without affecting cell division, and slows enterocytic migration along crypt-villus units. The effects produced by Rac1Leu61 or Rac1Asn17 in the 129/Sv epithelium do not spread to adjacent normal C57Bl/6 epithelial cells. These results provide in vivo evidence that Rac1 is involved in the import and intracellular processing of signals that control differentiation of a mammalian epithelium.
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KLEIN, J. "T-lymphopoietic capacity of the mouse intestinal epithelium." Seminars in Immunology 7, no. 5 (October 1995): 291–97. http://dx.doi.org/10.1016/1044-5323(95)90010-1.
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Li, Y. Q., S. A. Roberts, U. Paulus, M. Loeffler, and C. S. Potten. "The crypt cycle in mouse small intestinal epithelium." Journal of Cell Science 107, no. 12 (December 1, 1994): 3271–79. http://dx.doi.org/10.1242/jcs.107.12.3271.
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We have used a mutation-induced marker system in the intestine of mice heterozygous at the Dlb-1 locus, which determines the expression of binding sites for the lectin Dolichos biflorus agglutinin, and the frequency of clustering of mutated crypts with time as a means of investigating the frequency of the crypt fission process and the crypt cycle. Whole-mount preparations from heterozygous Dlb-1b/Dlb-1a mice were stained with a peroxidase conjugate of Dolichos biflorus agglutinin. Mutations at the Dlb-1b locus in crypt stem cells result in loss of DBA-Px binding in these cells and subsequently their progeny, which eventually results in a rare isolated single, unstained crypt. The subsequent development of pairs, triplets and clusters of negative staining crypts has been assumed to be the result of crypt fission. The frequency of these fission events has been measured in control untreated mice. These negative crypts are the result of spontaneous mutations. We have also looked at mutated crypts after treatment with N-nitroso-N-ethylurea or N-methyl-N'-nitro-N-nitrosoguanidine of young adult mice, which elevates the number of mutations. Our results suggest that the crypt cycle in control animals is very long, 187 +/- 44 weeks (3.6 years, i.e. essentially the life of a laboratory mouse). This implies that about a third of the crypts may divide once in the life of a mouse. After sufficient time for conversion of mixed crypts to monophenotypic crypts after mutagen treatment several clusters of negative crypts were seen.(ABSTRACT TRUNCATED AT 250 WORDS)
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Gulati, Ajay S., Scott A. Ochsner, and Susan J. Henning. "Molecular properties of side population-sorted cells from mouse small intestine." American Journal of Physiology-Gastrointestinal and Liver Physiology 294, no. 1 (January 2008): G286—G294. http://dx.doi.org/10.1152/ajpgi.00416.2007.
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The high rate of turnover of the intestinal epithelium is maintained by a group of stem cells that reside at the base of the crypts of Lieberkuhn. Whereas the existence of these intestinal epithelial stem cells has been well established, their study has been limited due to the inability to isolate them. Previous work has utilized side population (SP) sorting of the murine small intestine to isolate a viable fraction of cells enriched for putative intestinal epithelial stem cells. In the present study, we have used gene expression profiling techniques to characterize the molecular features of this potential stem cell population. Further in situ hybridization studies reveal that transcripts enriched in the SP tend to localize to the intestinal crypt base/progenitor cell zone, while deenriched transcripts localize outside of this region. From a functional standpoint, gene ontology and pathway mapping analyses demonstrate that immune, mesenchymal, and differentiated epithelial cells are depleted in the SP fraction, while putative progenitor cells are enriched in this cell population. Furthermore, the significance of the maturity onset diabetes of the young pathway in these cells suggests that enteroendocrine progenitors are enriched in this cell fraction as well. In conclusion, SP sorting of mouse small intestinal mucosa does appear to isolate cells with progenitor characteristics. These findings provide the foundation for membrane protein-based sorting procedures that can be used to further fractionate these cells for transplantation experiments in the future.
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Forteza, Radia, Yolanda Figueroa, Anastasia Mashukova, Vipin Dulam, and Pedro J. Salas. "Conditional knockout of polarity complex (atypical) PKCι reveals an anti-inflammatory function mediated by NF-κB." Molecular Biology of the Cell 27, no. 14 (July 15, 2016): 2186–97. http://dx.doi.org/10.1091/mbc.e16-02-0086.
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The conserved proteins of the polarity complex made up of atypical PKC (aPKC, isoforms ι and ζ), Par6, and Par3 determine asymmetry in several cell types, from Caenorhabditis elegans oocytes to vertebrate epithelia and neurons. We previously showed that aPKC is down-regulated in intestinal epithelia under inflammatory stimulation. Further, expression of constitutively active PKCι decreases NF-κB activity in an epithelial cell line, the opposite of the effect reported in other cells. Here we tested the hypothesis that aPKC has a dual function in epithelia, inhibiting the NF-κB pathway in addition to having a role in apicobasal polarity. We achieved full aPKC down-regulation in small intestine villi and colon surface epithelium using a conditional epithelium-specific knockout mouse. The results show that aPKC is dispensable for polarity after cell differentiation, except for known targets, including ROCK and ezrin, claudin-4 expression, and barrier permeability. The aPKC defect resulted in increased NF-κB activity, which could be rescued by IKK and ROCK inhibitors. It also increased expression of proinflammatory cytokines. In contrast, expression of anti-inflammatory IL-10 decreased. We conclude that epithelial aPKC acts upstream of multiple mechanisms that participate in the inflammatory response in the intestine, including, but not restricted to, NF-κB.
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Stahl, Martin, Emilisa Frirdich, Jenny Vermeulen, Yuliya Badayeva, Xiaoxia Li, Bruce A. Vallance, and Erin C. Gaynor. "The Helical Shape of Campylobacter jejuni PromotesIn VivoPathogenesis by Aiding Transit through Intestinal Mucus and Colonization of Crypts." Infection and Immunity 84, no. 12 (September 19, 2016): 3399–407. http://dx.doi.org/10.1128/iai.00751-16.
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Campylobacter jejuniis a helix-shaped enteric bacterial pathogen and a common cause of gastroenteritis. We recently developed a mouse model for this human pathogen utilizing the SIGIRR-deficient mouse strain, which exhibits significant intestinal inflammation in response to intestinalC. jejuniinfection. In the current study, this mouse model was used to define whetherC. jejuni's characteristic helical shape plays a role in its ability to colonize and elicit inflammation in the mouse intestine. Mice were infected with the previously characterized straight-rod Δpgp1and Δpgp2mutant strains, along with a newly characterized curved-rod Δ1228mutant strain. We also compared the resultant infections and pathology to those elicited by the helix-shaped wild-typeC. jejuniand complemented strains. Despite displaying wild-type colonization of the intestinal lumen, the straight-rod Δpgp1and Δpgp2mutants were essentially nonpathogenic, while all strains with a curved or helical shape retained their expected virulence. Furthermore, analysis ofC. jejunilocalization within the ceca of infected mice determined that the primary difference between the rod-shaped, nonpathogenic mutants and the helix-shaped, pathogenic strains was the ability to colonize intestinal crypts. Rod-shaped mutants appeared unable to colonize intestinal crypts due to an inability to pass through the intestinal mucus layer to directly contact the epithelium. Together, these results support a critical role forC. jejuni's helical morphology in enabling it to traverse and colonize the mucus-filled intestinal crypts of their host, a necessary step required to trigger intestinal inflammation in response toC. jejuni.
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Petrof, Elaine O., Mark W. Musch, Mae Ciancio, Jun Sun, Michael E. Hobert, Erika C. Claud, Andrew Gewirtz, and Eugene B. Chang. "Flagellin is required for salmonella-induced expression of heat shock protein Hsp25 in intestinal epithelium." American Journal of Physiology-Gastrointestinal and Liver Physiology 294, no. 3 (March 2008): G808—G818. http://dx.doi.org/10.1152/ajpgi.00362.2007.
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Flagellin is a bacterial protein responsible for activation of Toll-like receptor 5 (TLR5), which we hypothesize is involved in Salmonella's induction of cytoprotective heat shock proteins in intestinal epithelial cells. Flagellin induces the cytoprotective heat shock protein Hsp25 in different intestinal epithelial cell lines and in mouse intestine. Flagellin induces Hsp25 expression in a time-dependent manner in vitro. This effect is transcriptional, as confirmed by luciferase reporter assays and actinomycin D treatment. In addition, Hsp25 induction requires p38 MAPK activation and is only observed when flagellin is added to the basolateral side of polarized intestinal epithelial cells, consistent with the known location of TLR5. Flagellin-mediated Hsp25 induction is associated with increased protective effects against oxidant stress, an effect that is at least partially mediated by p38 MAPK. Use of small interfering RNA against Hsp25 demonstrates that flagellin-mediated protection against oxidant stress is to some degree mediated through Hsp25 induction. This suggests that, by protecting against oxidant injury, the induction of Hsp25 expression by flagellin may contribute to intestinal homeostasis. In a coculture cell model and in a mouse model of Salmonella enterica Serovar Typhimurium infection, not only does infection with wild-type and a flagellin-deletion mutant strain of Salmonella show that flagellin induces Hsp25 in vivo, but it also demonstrates that in the case of live Salmonella infection, flagellin serves as a major stimulus for the induction of Hsp25 expression. These data provide evidence that flagellin is required for Salmonella-mediated induction of Hsp25 expression in intestinal epithelium.
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Hendrickson, Barbara A., Jun Guo, Robert Laughlin, Yimei Chen, and John C. Alverdy. "Increased Type 1 Fimbrial Expression among Commensal Escherichia coli Isolates in the Murine Cecum following Catabolic Stress." Infection and Immunity 67, no. 2 (February 1, 1999): 745–53. http://dx.doi.org/10.1128/iai.67.2.745-753.1999.
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ABSTRACT Although indigenous bacteria intimately colonize the intestinal mucosa, under normal conditions the intestinal epithelial cell is free of adherent bacteria. Nonetheless, commensal bacteria such asEscherichia coli adhere to and translocate across the intestinal epithelium in association with a number of pathologic states including hemorrhagic shock, immunosuppression, traumatic tissue injury, and lack of enteral feedings. The adhesins involved in the adherence of indigenous E. coli to the intestinal epithelium in vivo following catabolic stress are unknown. We have developed a mouse model to study the bacterial adhesins which mediate the increased intestinal adherence of E. coliafter partial hepatectomy and short-term starvation. Our studies demonstrated that hepatectomy and starvation in the mouse were associated with a 7,500-fold increase in the numbers of E. coli bacteria adhering to the cecum. In addition, erythrocyte agglutination studies, as well as immunostaining of fimbrial preparations and electron micrographs of the bacteria, revealed that surface type 1 fimbriae were more abundant in the commensal E. coli harvested from the ceca of the stressed mice. These E. coli isolates adhered to a mouse colon cell line and injected cecal loops in a mannose-inhibitable manner, which suggests a role for type 1 fimbriae in the adherence of the E. coli isolates to the cecum in vivo following host catabolic stress.
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Rankin, Erinn B., Wei Xu, Debra G. Silberg, and EunRan Suh. "Putative intestine-specific enhancers located in 5′ sequence of the CDX1 gene regulate CDX1 expression in the intestine." American Journal of Physiology-Gastrointestinal and Liver Physiology 286, no. 5 (May 2004): G872—G880. http://dx.doi.org/10.1152/ajpgi.00326.2003.
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CDX1 is a homeobox transcription factor that plays a critical role in intestinal epithelial cell growth and differentiation. CDX1 gene expression is tightly regulated in a temporal and cell-type specific manner. However, very little is known about the regulatory mechanisms that direct CDX1 gene expression in the intestine. To elucidate these mechanisms, we employed a series of transgenic mouse studies using the 5′ flanking sequences of the human CDX1 gene. Transgenic mice containing nucleotides between -5667 and +68 relative to the transcription start site of the CDX1 gene demonstrated ectopic expression of the transgene in the brain and gastric smooth muscle. However, transgenic expression of the nucleotides -15601 to +68 of the CDX1 gene was restricted to the intestinal epithelium, which was identical to endogenous CDX1 gene expression. Taken together, the upstream sequences between -15601 and -5667 contain regulatory elements that direct transgene expression specifically to the intestinal epithelium. Furthermore, DNase I hypersensitivity assays revealed two active chromatin regions in the CDX1 gene (hypertensive sites 1 and 2) located at approximately -5.8 and -6.8 kb upstream of the CDX1 gene, respectively, which may function as potential intestine-specific enhancers.
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Del Buono, R., K. A. Fleming, A. L. Morey, P. A. Hall, and N. A. Wright. "A nude mouse xenograft model of fetal intestine development and differentiation." Development 114, no. 1 (January 1, 1992): 67–73. http://dx.doi.org/10.1242/dev.114.1.67.
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This report describes a novel in vivo model of intestinal differentiation. Fourteen day, undifferentiated fetal rat small intestine, stripped of the major part of its mesenchyme, suspended in a type I collagen gel and then xenografted into a nude mouse, undergoes small intestinal morphogenesis and cytodifferentiation. All four major epithelial lineages, namely Paneth, goblet, columnar and endocrine are present. Double-label nonisotopic in situ hybridization, employing biotinylated and digoxigenin-labelled whole rat DNA and whole mouse DNA probes, was performed to distinguish donor cells from host cell types. The outer longitudinal smooth muscle layer, and the major part of the lamina propria, including pericryptal fibroblasts, are of host mouse origin; the inner circular smooth muscle layer is of donor rat origin. Cells of the muscularis propria and lamina propria acquired smooth muscle alpha-actin, presumably under the influence of the donor endoderm. Furthermore, this xenograft develops a host vascular network, and cells with the morphological appearance of lymphocytes are present within the intestinal epithelium. The production of chemotactic factors by the endoderm is postulated because grafting of collagen gel alone results in a minimal invasion by stromal cells which do not express smooth muscle alpha-actin.
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Bjerknes, Matthew, and Hazel Cheng. "Cell Lineage metastability in Gfi1-deficient mouse intestinal epithelium." Developmental Biology 345, no. 1 (September 2010): 49–63. http://dx.doi.org/10.1016/j.ydbio.2010.06.021.
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Morvay, Petruta L., Myriam Baes, and Paul P. Van Veldhoven. "Differential activities of peroxisomes along the mouse intestinal epithelium." Cell Biochemistry and Function 35, no. 3 (March 29, 2017): 144–55. http://dx.doi.org/10.1002/cbf.3255.
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Ouellette, A. J., R. M. Greco, M. James, D. Frederick, J. Naftilan, and J. T. Fallon. "Developmental regulation of cryptdin, a corticostatin/defensin precursor mRNA in mouse small intestinal crypt epithelium." Journal of Cell Biology 108, no. 5 (May 1, 1989): 1687–95. http://dx.doi.org/10.1083/jcb.108.5.1687.
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Cryptdin mRNA codes for the apparent precursor to a corticostatin/defensin-related peptide that accumulates to high levels in mouse intestinal crypt epithelium during postnatal development. The primary structure, intestinal cell distribution, and developmental appearance of cryptdin mRNA have been determined. Cryptdin mRNA is 450-480 nucleotides long. Translation of the partial cryptdin cDNA sequence reveals a 70-amino acid open reading frame that includes 32 carboxy-terminal residues that align with those in the consensus sequence, C.CR...C....ER..G.C....CCR, which is a common feature of leukocyte defensins and lung corticostatins (Selsted, M. E., D. M. Brown, R. J. DeLange, S. S. L. Harwig, and R. I. Lehrer. 1985. J. Biol. Chem. 260:4579-4584; Zhu, Q., J. Hu, S. Mulay, F. Esch, S. Shimasaki, and S. Solomon. 1988. Proc. Natl. Acad. Sci. USA. 85:592-596). In situ hybridization of cryptdin cDNA to paraformaldehyde-fixed, frozen sections of adult jejunum and ileum showed intense and specific labeling of epithelial cells in the base of all crypts. Analysis of sections from suckling mice showed that cryptdin mRNA is detectable in 10-20% of crypts in 10-d-old mice, in approximately 80% of crypts in 16-d-old mice, and in all crypts of mice 20 d and older. During the fourth week, the sequence accumulates in crypts to the maximal adult level. Cryptdin mRNA content in adult small intestine is independent both of T cell involvement and luminal bacteria. The role of cryptdin in small bowel physiology remains to be determined: cryptdin may inhibit bacterial translocation, modulate intestinal hormone synthesis, influence hormonal sensitivity of the intestinal epithelium, or exhibit a multiplicity of related activities.
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Maywald, Rebecca L., Stephanie K. Doerner, Luca Pastorelli, Carlo De Salvo, Susan M. Benton, Emily P. Dawson, Denise G. Lanza, et al. "IL-33 activates tumor stroma to promote intestinal polyposis." Proceedings of the National Academy of Sciences 112, no. 19 (April 27, 2015): E2487—E2496. http://dx.doi.org/10.1073/pnas.1422445112.
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Tumor epithelial cells develop within a microenvironment consisting of extracellular matrix, growth factors, and cytokines produced by nonepithelial stromal cells. In response to paracrine signals from tumor epithelia, stromal cells modify the microenvironment to promote tumor growth and metastasis. Here, we identify interleukin 33 (IL-33) as a regulator of tumor stromal cell activation and mediator of intestinal polyposis. In human colorectal cancer, IL-33 expression was induced in the tumor epithelium of adenomas and carcinomas, and expression of the IL-33 receptor, IL1RL1 (also referred to as IL1-R4 or ST2), localized predominantly to the stroma of adenoma and both the stroma and epithelium of carcinoma. Genetic and antibody abrogation of responsiveness to IL-33 in the ApcMin/+ mouse model of intestinal tumorigenesis inhibited proliferation, induced apoptosis, and suppressed angiogenesis in adenomatous polyps, which reduced both tumor number and size. Similar to human adenomas, IL-33 expression localized to tumor epithelial cells and expression of IL1RL1 associated with two stromal cell types, subepithelial myofibroblasts and mast cells, in ApcMin/+ polyps. In vitro, IL-33 stimulation of human subepithelial myofibroblasts induced the expression of extracellular matrix components and growth factors associated with intestinal tumor progression. IL-33 deficiency reduced mast cell accumulation in ApcMin/+ polyps and suppressed the expression of mast cell-derived proteases and cytokines known to promote polyposis. Based on these findings, we propose that IL-33 derived from the tumor epithelium promotes polyposis through the coordinated activation of stromal cells and the formation of a protumorigenic microenvironment.
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Kamiya, Sato, Kaori Shimizu, Ayaka Okada, and Yasuo Inoshima. "Induction of Serum Amyloid A3 in Mouse Mammary Epithelial Cells Stimulated with Lipopolysaccharide and Lipoteichoic Acid." Animals 11, no. 6 (May 25, 2021): 1548. http://dx.doi.org/10.3390/ani11061548.
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In this study, to establish whether serum amyloid A (SAA) 3 plays a role in the defense against bacterial infection in mouse mammary epithelium, normal murine mammary gland (NMuMG) epithelial cells were stimulated with lipopolysaccharide (LPS) and lipoteichoic acid (LTA). LPS and LTA significantly enhanced mRNA expression level of the Saa3 gene, whereas no significant change was observed in the Saa1 mRNA level. Furthermore, LPS induced SAA3 protein expression more strongly than LTA, whereas neither LPS nor LTA significantly affected SAA1 protein expression. These data indicate that the expression of SAA3 in mouse mammary epithelial cells was increased by the stimulation with bacterial antigens. SAA3 has been reported to stimulate neutrophils in the intestinal epithelium and increase interleukin-22 expression, which induces activation of the innate immune system and production of antibacterial proteins, such as antimicrobial peptides. Therefore, collectively, these data suggest that SAA3 is involved in the defense against bacterial infection in mouse mammary epithelium.
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Kim, S. H., K. A. Roth, A. R. Moser, and J. I. Gordon. "Transgenic mouse models that explore the multistep hypothesis of intestinal neoplasia." Journal of Cell Biology 123, no. 4 (November 15, 1993): 877–93. http://dx.doi.org/10.1083/jcb.123.4.877.
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SV-40 T antigen (TAg), human K-rasVal12, and a dominant negative mutant of human p53 (p53Ala143) have been expressed singly and in all possible combinations in postmitotic enterocytes distributed throughout the duodenal-colonic axis of 1-12-mo-old FVB/N transgenic mice to assess the susceptibility of this lineage to gene products implicated in the pathogenesis of human gut neoplasia. SV-40 TAg produces re-entry into the cell cycle. Transgenic pedigrees that produce K-rasVal12 alone, p53Ala143 alone, or K-rasVal12 and p53Ala143 have no detectable phenotypic abnormalities. However, K-rasVal12 cooperates with SV-40 TAg to generate marked proliferative and dysplastic changes in the intestinal epithelium. These abnormalities do not progress to form adenomas or adenocarcinomas over a 9-12-mo period despite sustained expression of the transgenes. Addition of p53Ala143 to enterocytes that synthesize SV-40 TAg and K-rasVal12 does not produce any further changes in proliferation or differentiation. Mice that carry one, two, or three of these transgenes were crossed to animals that carry Min, a fully penetrant, dominant mutation of the Apc gene associated with the development of multiple small intestinal and colonic adenomas. A modest (2-5-fold) increase in tumor number was noted in animals which express SV-40 TAg alone, SV-40 TAg and K-rasVal12, or SV-40 TAg, K-rasVal12 and p53Ala143. However, the histopathologic features of the adenomas were not altered and the gut epithelium located between tumors appeared similar to the epithelium of their single transgenic, bi-transgenic, or tri-transgenic parents without Min. These results suggest that (a) the failure of the dysplastic gut epithelium of SV-40 TAg X K-rasVal12 mice to undergo further progression to adenomas or adenocarcinomas is due to the remarkable protective effect of a continuously and rapidly renewing epithelium, (b) initiation of tumorigenesis in Min mice typically occurs in crypts rather than in villus-associated epithelial cell populations, and (c) transgenic mouse models of neoplasia involving members of the enterocytic lineage may require that gene products implicated in tumorigenesis be directed to crypt stem cells or their immediate descendants. Nonetheless, directing K-rasVal12 production to proliferating and nonproliferating cells in the lower and upper half of small intestinal and colonic crypts does not result in any detectable abnormalities.
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Frochot, Vincent, Malik Alqub, Anne-Laure Cattin, Véronique Carrière, Anne Houllier, Floriane Baraille, Laurence Barbot, et al. "The transcription factor HNF-4α: a key factor of the intestinal uptake of fatty acids in mouse." American Journal of Physiology-Gastrointestinal and Liver Physiology 302, no. 11 (June 1, 2012): G1253—G1263. http://dx.doi.org/10.1152/ajpgi.00329.2011.
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With an excessive postprandial accumulation of intestine-derived, triglyceride-rich lipoproteins being a risk factor of cardiovascular diseases, it is essential to characterize the mechanisms controlling the intestinal absorption of dietary lipids. Our aim was to investigate the role of the transcription factor hepatocyte nuclear factor (HNF)-4α in this process. We used transgenic mice with a specific and inducible intestinal knockout of Hnf-4α gene. One hour after a lipid bolus, in the presence of the lipase inhibitor tyloxapol, lower amounts of triglycerides were found in both plasma and intestinal epithelium of the intestine-specific Hnf-4α knockout (Hnf-4αintΔ) mice compared with the Hnf-4αloxP/loxP control mice. These discrepancies were due to a net decrease of the intestinal uptake of fatty acid in Hnf-4αintΔ mice compared with Hnf-4αloxP/loxP mice, as assessed by the amount of radioactivity that was recovered in intestine and plasma after gavage with labeled triolein or oleic acid, or in intestinal epithelial cells isolated from jejunum after a supply of labeled oleic acid-containing micelles. This decreased fatty acid uptake was associated with significant lower levels of the fatty acid transport protein-4 mRNA and protein along the intestinal tract and with a lower acyl-CoA synthetase activity in Hnf-4αintΔ mice compared with the control mice. We conclude that the transcription factor HNF-4α is a key factor of the intestinal absorption of dietary lipids, which controls this process as early as in the initial step of fatty acid uptake by enterocytes.
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Wang, C., L. Yao, Y. Zhang, and Q. Cao. "P057 CRL4DCAF2 promotes cell proliferation and limits the development of colitis." Journal of Crohn's and Colitis 15, Supplement_1 (May 1, 2021): S163—S164. http://dx.doi.org/10.1093/ecco-jcc/jjab076.186.
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Abstract Background Ulcerative colitis (UC) is an idiopathic intestinal inflammatory disease, which leads to chronic intestinal mucosal barrier damage. More and more evidences show that ubiquitination of proteins regulates the occurrence and development of intestinal inflammation. DCAF family proteins could form E3 ubiquitin ligase with CRL4-DDB1 to regulate cell growth, differentiation, apoptosis and other life activities. CRL4DCAF2 is a crucial regulator in cell cycle regulation, but there are few studies on its application in intestinal epithelium. This study aims to explore the specific mechanism of CRL4DCAF2 in regulating the proliferation and repairment of intestinal epithelial cells. Methods DSS - induced colitis in mice was used as the experimental model in vivo. HCT116 and SW480 cell lines were used as experimental models in vitro studies.The Cre-loxP system was used to construct a mouse model of intestinal epithelium-specific DCAF2 knockout. The intestinal mucosa biopsy specimens of 11 normal patients and 11 UC patients were collected. In addition, qRT-PCR, Western blot, RNA-seq and immunofluorescent staining were used to detect the expression levels of target genes in human colon biopsy specimens, mouse colon tissues, HCT116 or SW480 cells Results DCAF2 gene was highly expressed in the colon of mice. The occurrence and development of DSS-induced experimental colitis was accompanied by a significant down-regulation of DCAF2 protein expression in colon. DCAF2 mRNA level was significantly decreased in UC patients. Mouse with intestinal epithelial-specific knockout of DCAF2(i.e. DCAF2IEC-KO) suffered from embryonic death. Compared with wild-type adult C57BL/6J mice, DCAF2IEC-KD mouse showed more severe intestinal inflammation in DSS-induced colitis model. CCK-8 test, PI staining and EDU staining flow cytometry experiments showed that the proliferation of intestinal epithelial cells with DCAF2 overexpression was faster than that of the control (P < 0.05) in HCT116 and SW480 cell lines, while in knockdown of DCAF2 models, the opposite results were obtained. Its effect may be related to the ubiquitination of p21. At the same time, MLN4924 in vivo and in vitro experiments further verified our experimental results. Combined with RNA-seq and Western blot, we also found that DCAF2 may reduce the symptoms of colitis by maintaining the stability of autophagy. Conclusion DCAF2 is low expressed in patients with ulcerative colitis, which may promote the activation and proliferation of intestinal epithelial cells. It could maintain autophagy stability, and restore intestinal barrier, thus alleviate the development of ulcerative colitis
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Wittkopf, Nadine, Claudia Günther, Eva Martini, Maximilian Waldner, Kerstin U. Amann, Markus F. Neurath, and Christoph Becker. "Lack of Intestinal Epithelial Atg7 Affects Paneth Cell Granule Formation but Does Not Compromise Immune Homeostasis in the Gut." Clinical and Developmental Immunology 2012 (2012): 1–9. http://dx.doi.org/10.1155/2012/278059.
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Genetic polymorphisms of autophagy-related genes have been associated with an increased risk to develop inflammatory bowel disease (IBD). Autophagy is an elementary process participating in several cellular events such as cellular clearance and nonapoptotic programmed cell death. Furthermore, autophagy may be involved in intestinal immune homeostasis due to its participation in the digestion of intracellular pathogens and in antigen presentation. In the present study, the role of autophagy in the intestinal epithelial layer was investigated. The intestinal epithelium is essential to maintain gut homeostasis, and defects within this barrier have been associated with the pathogenesis of IBD. Therefore, mice with intestinal epithelial deletion of Atg7 were generated and investigated in different mouse models. Knockout mice showed reduced size of granules and decreased levels of lysozyme in Paneth cells. However, this was dispensable for gut immune homeostasis and had no effect on susceptibility in mouse models of experimentally induced colitis.
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Maier, Elizabeth A., Mary R. Dusing, and Dan A. Wiginton. "Temporal Regulation of Enhancer Function in Intestinal Epithelium." Journal of Biological Chemistry 281, no. 43 (August 31, 2006): 32263–71. http://dx.doi.org/10.1074/jbc.m606699200.
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An intestine-specific gene regulatory region was previously identified near the second exon of the human adenosine deaminase (ADA) gene. In mammalian intestine, ADA is expressed at high levels only along the villi of the duodenal epithelium, principally if not exclusively in enterocytes. Within the ADA intestinal regulatory region, a potent duodenum-specific enhancer was identified that controls this pattern of expression. This enhancer has been shown to rely on PDX-1, GATA factors, and Cdx factors for its function. Upstream of the enhancer, a separate temporal regulatory region was identified that has no independent enhancer capability but controls the timing of enhancer activation. DNase I footprinting and electrophoretic mobility shift assays were used to begin to characterize temporal region function at the molecular level. In this manner, binding sites for the Onecut (OC) family of factors, YY1, and NFI family members were identified. Identification of the OC site was especially interesting, because almost nothing is known about the function of OC factors in intestine. In transgenic mice, mutation of the OC site to ablate binding resulted in a delay of 2–3 weeks in enhancer activation in the developing postnatal intestine, a result very similar to that observed previously when the entire temporal region was deleted. In mammals, the OC family is comprised of OC-1/HNF-6, OC-2, and OC-3. An examination of intestinal expression patterns showed that all three OC factors are expressed at detectable levels in adult mouse duodenum, with OC-2 predominant. In postnatal day 2 mice only OC-2 and OC-3 were detected in intestine, with OC-2 again predominant.
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Tremblay, S., R. Girard, C. Noll, A. Carpentier, and F. Boudreau. "A267 ROLE OF INTESTINAL EPITHELIAL NUCLEAR RECEPTOR HNF4A DURING METABOLIC DISORDERS." Journal of the Canadian Association of Gastroenterology 3, Supplement_1 (February 2020): 144–45. http://dx.doi.org/10.1093/jcag/gwz047.266.
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Abstract Background HNF4α belongs to the hormone nuclear receptor family and is expressed in liver, intestinal epithelium and pancreas where it regulates genes involved in the control of metabolism. Inactivating mutations in the HNF4A gene cause several forms of maturity-onset diabetes of the young (MODY). However, the specific deletion of Hnf4a in mouse pancreatic beta cells does not lead to diabetes, suggesting the contribution of other tissues, such as the intestine, are necessary for the progression of the disease. Aims Our main hypothesis was that intestinal epithelial HNF4α regulates gene products that act through a paracrine mode of communication in the context of glucose metabolism. The aims of this study were to investigate the impact of deleting Hnf4a in the mouse intestinal epithelium during glucose homeostasis and to identify molecular mechanisms involved during glucose-induced obesity resistance. Methods The Villin-Cre recombinase transgenic mouse model was used to conditionally delete Hnf4a in the intestinal epithelium (Hnf4adeltaIEC). Hnf4adeltaIEC mice were put on a high sugar diet for 8 to 12 weeks, using a 30% sucrose supplemented ab lithium water. Blood glucose values in controls and mutants were measured from whole venous blood from fasted mice or during glucose and insulin tolerance tests. Mouse serum hormone levels (Ghrelin, Fibroblast-growth factor-15 (Fgf15), Insulin, Cholecystokinin (CCK), etc.) were measured using mouse ELISA kits. The Promethion High-Definition Room Calorimetry System was used for indirect calorimetry and metabolic studies. Results Both male and female Hnf4adeltaIEC mice displayed a metabolic resistance to develop obesity under sucrose supplementation when compared to control mice. While male mutant mice showed a resistance to obesity after only 2 weeks of treatment, female mutant mice took at least 6 weeks to display some resistance. The gut hormones ghrelin and Fgf15 were also found modified in fasted mutant mice. Female mutant mice presented a significant increase of 1.8 fold in circulating Fgf15 and an increase of 1.4 fold in circulating ghrelin. Similar changes were observed in male mutant mice. However, only male mutant mice presented an insulin resistance and an oral glucose tolerance after between 6 and 8 weeks. Brown adipose tissue (BAT) whitening was observed after 8 weeks of sucrose treatment in control obese animals, a condition that was prevented in Hnf4adeltaIEC mice. Conclusions The identification of paracrine intestinal targets for HNF4α in association with glucose metabolism will provide a better understanding of the molecular nature of tissues crosstalk in energy balance and in metabolism disorders including diabetes and obesity. Funding Agencies CIHR
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Munson, Scott, Yongmei Wang, Wenhan Chang, and Daniel D. Bikle. "Myosin 1a Regulates Osteoblast Differentiation Independent of Intestinal Calcium Transport." Journal of the Endocrine Society 3, no. 11 (August 12, 2019): 1993–2011. http://dx.doi.org/10.1210/js.2019-00171.
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Abstract Myosin 1A (Myo1a) is a mechanoenzyme previously thought to be located exclusively in the intestinal epithelium. It is the principle calmodulin-binding protein of the brush border. Based on earlier studies in chickens, we hypothesized that Myo1a facilitates calcium transport across the brush border membrane of the intestinal epithelium, perhaps in association with the calcium channel Trpv6. Working with C2Bbe1 cells, a human intestinal epithelial cell line, we observed that overexpression of Myo1a increased, whereas the antisense construct blocked calcium transport. To further test this hypothesis, we examined mice in which either or both Myo1a and Trpv6 had been deleted. Although the Trpv6-null mice had decreased intestinal calcium transport, the Myo1a-null mouse did not, disproving our original hypothesis, at least in mice. Expecting that a reduction in intestinal calcium transport would result in decreased bone, we examined the skeletons of these mice. To our surprise, we found no decrease in bone in the Trpv6-null mouse, but a substantial decrease in the Myo1a-null mouse. Double deletions were comparable to the Myo1a null. Moreover, Myo1a but not Trpv6 was expressed in osteoblasts. In vitro, the bone marrow stromal cells from the Myo1a-null mice showed normal numbers of colony-forming units but marked decrements in the formation of alkaline phosphatase–positive colonies and mineralized nodules. We conclude that Myo1a regulates osteoblast differentiation independent of its role, if any, in intestinal calcium transport, whereas Trpv6 functions primarily to promote intestinal calcium transport with little influence in osteoblast function.
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George, Michelle M., Mushfiqur Rahman, Jessica Connors, and Andrew W. Stadnyk. "Opinion: Are Organoids the End of Model Evolution for Studying Host Intestinal Epithelium/Microbe Interactions?" Microorganisms 7, no. 10 (September 29, 2019): 406. http://dx.doi.org/10.3390/microorganisms7100406.
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In the pursuit to understand intestinal epithelial cell biology in health and disease, researchers have established various model systems, from whole animals (typically rodents) with experimentally induced disease to transformed human carcinomas. The obvious limitation to the ex vivo or in vitro cell systems was enriching, maintaining, and expanding differentiated intestinal epithelial cell types. The popular concession was human and rodent transformed cells of mainly undifferentiated cells, with a few select lines differentiating along the path to becoming goblet cells. Paneth cells, in particular, remained unculturable. The breakthrough came in the last decade with the report of conditions to grow mouse intestinal organoids. Organoids are 3-dimensional ex vivo “mini-organs” of the organ from which the stem cells were derived. Intestinal organoids contain fully differentiated epithelial cells in the same spatial organization as in the native epithelium. The cells are suitably polarized and produce and secrete mucus onto the apical surface. This review introduces intestinal organoids and provide some thoughts on strengths and weaknesses in the application of organoids to further advance our understanding of the intestinal epithelial–microbe relationship.
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Montgomery, Robert K., Diana L. Carlone, Camilla A. Richmond, Loredana Farilla, Mariette E. G. Kranendonk, Daniel E. Henderson, Nana Yaa Baffour-Awuah, et al. "Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells." Proceedings of the National Academy of Sciences 108, no. 1 (December 20, 2010): 179–84. http://dx.doi.org/10.1073/pnas.1013004108.
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The intestinal epithelium is maintained by a population of rapidly cycling (Lgr5+) intestinal stem cells (ISCs). It has been postulated, however, that slowly cycling ISCs must also be present in the intestine to protect the genome from accumulating deleterious mutations and to allow for a response to tissue injury. Here, we identify a subpopulation of slowly cycling ISCs marked by mouse telomerase reverse transcriptase (mTert) expression that can give rise to Lgr5+ cells. mTert-expressing cells distribute in a pattern along the crypt–villus axis similar to long-term label-retaining cells (LRCs) and are resistant to tissue injury. Lineage-tracing studies demonstrate that mTert+ cells give rise to all differentiated intestinal cell types, persist long term, and contribute to the regenerative response following injury. Consistent with other highly regenerative tissues, our results demonstrate that a slowly cycling stem cell population exists within the intestine.
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Walrath, Travis, Robert A. Malizia, Xinjun Zhu, Stephen P. Sharp, Shanti S. D'Souza, Reynold Lopez-Soler, Brian Parr, et al. "IFN-γ and IL-17A regulate intestinal crypt production of CXCL10 in the healthy and inflamed colon." American Journal of Physiology-Gastrointestinal and Liver Physiology 318, no. 3 (March 1, 2020): G479—G489. http://dx.doi.org/10.1152/ajpgi.00208.2019.
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During intestinal inflammation, immature cells within the intestinal crypt are called upon to replenish lost epithelial cell populations, promote tissue regeneration, and restore barrier integrity. Inflammatory mediators including TH1/TH17-associated cytokines influence tissue health and regenerative processes, yet how these cytokines directly influence the colon crypt epithelium and whether the crypt remains responsive to these cytokines during active damage and repair, remain unclear. Here, using laser-capture microdissection and primary colon organoid culture, we show that the cytokine milieu regulates the ability of the colonic crypt epithelium to participate in proinflammatory signaling. IFN-γ induces the TH1-recruiting, proinflammatory chemokine CXCL10/IP10 in primary murine intestinal crypt epithelium. CXCL10 was also induced in colonic organoids derived from mice with active, experimentally induced colitis, suggesting that the crypt can actively secrete CXCL10 in select cytokine environments during colitis. Colon expression of cxcl10 further increased during infectious and noninfectious colitis in Il17a−/− mice, demonstrating that IL-17A exerts a negative effect on CXCL10 in vivo. Furthermore, IL-17A directly antagonized CXCL10 production in ex vivo organoid cultures derived from healthy murine colons. Interestingly, direct antagonism of CXCL10 was not observed in organoids derived from colitic mouse colons bearing active lesions. These data, highlighting the complex interplay between the cytokine milieu and crypt epithelia, demonstrate proinflammatory chemokines can be induced within the colonic crypt and suggest the crypt remains responsive to cytokine modulation during inflammation. NEW & NOTEWORTHY Upon damage, the intestinal epithelium regenerates to restore barrier function. Here we observe that the local colonic cytokine milieu controls the production of procolitic chemokines within the crypt base and colon crypts remain responsive to cytokines during inflammation. IFN-γ promotes, while IL-17 antagonizes, CXCL10 production in healthy colonic crypts, while responses to cytokines differ in inflamed colon epithelium. These data reveal novel insight into colon crypt responses and inflammation-relevant alterations in signaling.
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Clarke, A. R. "Cancer genetics: mouse models of intestinal cancer." Biochemical Society Transactions 35, no. 5 (October 25, 2007): 1338–41. http://dx.doi.org/10.1042/bst0351338.
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The capacity to model cancer within the mouse has advanced significantly in recent years. Perhaps the most notable technical gains have been in the development of techniques that allow the temporal and spatial control of gene expression, so that it is now possible to regulate target genes in the tissue of choice and at a given time [Maddison and Clarke (2005) J. Pathol. 205, 181–193; Shaw and Clarke (2007) DNA Repair 6, 1403–1412; Marsh and Clarke (2007) Expert Rev. Anticancer Ther. 7, 519–531]. We have used these approaches to study tumorigenesis in the murine intestine. Loss of function of the tumour-suppressor gene Apc (adenomatous polyposis coli) has been associated with the development of both human and murine neoplasia, principally those of the intestinal epithelium. However, as Apc has been implicated in multiple cellular functions, the precise mechanisms underlying these associations remain somewhat unclear. I review here the use of an inducible strategy to co-ordinately delete genes from the adult murine epithelium. This approach has allowed a characterization of the direct consequences of inactivation of gene function. For Apc, these include failure in the differentiation programme, failure to migrate, aberrant proliferation and the aberrant induction of apoptosis. Transcriptome analysis of this model has also identified potential new targets for therapeutic intervention, such as Sparc (secreted protein acidic and rich in cysteine), deficiency of which, we have now shown, suppresses adenoma formation. Finally, we have been able to address how other genes modulate the consequences of Apc loss. Thus we show that there is little effect following loss of cyclin D1, Tcf-1 and p53, but that there are marked differences following loss of either c-Myc or Mbd2. The models therefore allow us to define the earliest events associated with carcinogenesis in the intestine.
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Sutherland, Kate, Richard L. Young, Nicole J. Cooper, Michael Horowitz, and L. Ashley Blackshaw. "Phenotypic characterization of taste cells of the mouse small intestine." American Journal of Physiology-Gastrointestinal and Liver Physiology 292, no. 5 (May 2007): G1420—G1428. http://dx.doi.org/10.1152/ajpgi.00504.2006.
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Nutrient-evoked gastrointestinal reflexes are likely initiated by specialized epithelial cells located in the small intestine that detect luminal stimuli and release mediators that activate vagal endings. The G-protein α-gustducin, a key signal molecule in lingual taste detection, has been identified in mouse small intestine, where it may also subserve nutrient detection; however, the phenotype of α-gustducin cells is unknown. Immunohistochemistry was performed throughout the mouse small intestine for α-gustducin, enteroendocrine cell markers 5-HT and glucagon-like peptide-1 (GLP-1), and brush cell markers neuronal nitric oxide synthase and Ulex europaeus agglutinin-1 (UEA-1) lectin binding, singly, and in combination. α-Gustducin was expressed in solitary epithelial cells of the mid to upper villus, which were distributed in a regional manner with most occurring within the midjejunum. Here, 27% of α-gustducin cells colabeled for 5-HT and 15% for GLP-1; 57% of α-gustducin cells colabeled UEA-1, with no triple labeling. α-Gustducin cells that colabeled for 5-HT or GLP-1 were of distinct morphology and exhibited a different α-gustducin immunolabeling pattern to those colabeled with UEA-1. Neuronal nitric oxide synthase was absent from intestinal epithelium despite strong labeling in the myenteric plexus. We conclude that subsets of enteroendocrine cells in the midjejunum and brush cells (more generally distributed) are equipped to utilize α-gustducin signaling in mice. Intestinal taste modalities may be signaled by these enteroendocrine cells via the release of 5-HT, GLP-1, or coexpressed mediators or by brush cells via a nonnitrergic mediator in distinct regions of the intestine.
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Falk, P., R. G. Lorenz, N. Sharon, and J. I. Gordon. "Moluccella laevis lectin, a marker for cellular differentiation programs in mouse gut epithelium." American Journal of Physiology-Gastrointestinal and Liver Physiology 268, no. 4 (April 1, 1995): G553—G567. http://dx.doi.org/10.1152/ajpgi.1995.268.4.g553.
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We have assembled a system for testing the hypothesis that changes in glycoconjugate production represent markers for defining developmental, spatial, and environmental influences on the proliferation and differentiation programs of various mouse gut epithelial cell lineages. Multilabel immunohistochemical methods were used to survey the interactions of purified lectins with 1) normal fetal, neonatal, and adult FVB/N mouse gut, 2) gastric and intestinal isografts harvested at various developmental stages, and 3) transgenic mouse models of intestinal epithelial cell hyperplasia, dysplasia, and/or neoplasia. As a demonstration of the system's utility, we used the recently purified, alpha-N-acetyl-D-galactosamine-specific, Moluccella laevis lectin (MLL). In the adult FVB/N mouse stomach, MLL only recognizes glycoconjugates produced by a population of nonproliferating neck and prezymogenic cells that occupy a pivotal point in the complex, migration-associated differentiation program of the zymogenic cell lineage. In the developing FVB/N stomach, MLL binds to members of the zymogenic and pit lineages even before morphogenesis of gastric units is completed. Expression of MLL epitopes in pit cells is restricted to the period before the gastric epithelium has completed its morphoregulatory program. Analysis of gastric isografts indicates that these lineage- and developmental stage-specific patterns of glycoconjugate accumulation are not influenced by normal luminal contents. In the adult FVB/N intestine, MLL binding can be used to operationally define variations in the differentiation programs of 1) members of the enteroendocrine and goblet cell lineages during their migration along the crypt-to-villus axis and 2) cells comprising the follicle-associated epithelium overlying Peyer's patches. Accumulation of MLL epitopes in villus-associated enterocytes does not appear to be affected when these cells are induced to reenter the cell cycle by simian virus 40 large T antigen (SV40 TAg). MLL reactivity is not diminished when enterocytes begin to dedifferentiate as a result of production of SV40 TAg, human K-rasVal12, and a dominant negative human p53 mutant. The lack of change in MLL binding properties may reflect the brief residence time of enterocytes on the villus. These results indicate that glycoconjugate production represents a very useful tool for studying gut epithelial cell biology. Preliminary studies suggest that this is also true in the human gut.
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Hershberg, R., P. Eghtesady, B. Sydora, K. Brorson, H. Cheroutre, R. Modlin, and M. Kronenberg. "Expression of the thymus leukemia antigen in mouse intestinal epithelium." Proceedings of the National Academy of Sciences 87, no. 24 (December 1, 1990): 9727–31. http://dx.doi.org/10.1073/pnas.87.24.9727.
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Fujii, Tomoaki, Masaru Tamura, Shigekazu Tanaka, Yoriko Kato, Hiromi Yamamoto, Youichi Mizushina, and Toshihiko Shiroishi. "Gasdermin D (Gsdmd) is dispensable for mouse intestinal epithelium development." genesis 46, no. 8 (August 2008): 418–23. http://dx.doi.org/10.1002/dvg.20412.
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Winton, D. J., M. A. Blount, and B. A. J. Ponder. "A clonal marker induced by mutation in mouse intestinal epithelium." Nature 333, no. 6172 (June 1988): 463–66. http://dx.doi.org/10.1038/333463a0.
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Lee, Juneyoung, Attayeb Mohsen, Anik Banerjee, Louise D. McCullough, Kenji Mizuguchi, Motomu Shimaoka, Hiroshi Kiyono, and Eun Jeong Park. "Distinct Age-Specific miRegulome Profiling of Isolated Small and Large Intestinal Epithelial Cells in Mice." International Journal of Molecular Sciences 22, no. 7 (March 29, 2021): 3544. http://dx.doi.org/10.3390/ijms22073544.
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The intestinal epithelium serves as a dynamic barrier to protect the host tissue from exposure to a myriad of inflammatory stimuli in the luminal environment. Intestinal epithelial cells (IECs) encompass differentiated and specialized cell types that are equipped with regulatory genes, which allow for sensing of the luminal environment. Potential inflammatory cues can instruct IECs to undergo a diverse set of phenotypic alterations. Aging is a primary risk factor for a variety of diseases; it is now well-documented that aging itself reduces the barrier function and turnover of the intestinal epithelium, resulting in pathogen translocation and immune priming with increased systemic inflammation. In this study, we aimed to provide an effective epigenetic and regulatory outlook that examines age-associated alterations in the intestines through the profiling of microRNAs (miRNAs) on isolated mouse IECs. Our microarray analysis revealed that with aging, there is dysregulation of distinct clusters of miRNAs that was present to a greater degree in small IECs (22 miRNAs) compared to large IECs (three miRNAs). Further, miRNA–mRNA interaction network and pathway analyses indicated that aging differentially regulates key pathways between small IECs (e.g., toll-like receptor-related cascades) and large IECs (e.g., cell cycle, Notch signaling and small ubiquitin-related modifier pathway). Taken together, current findings suggest novel gene regulation pathways by epithelial miRNAs in aging within the gastrointestinal tissues.