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intestinal organoid

Marco Bardenbacher, Barbara Ruder, Nathalie Britzen-Laurent, Benjamin Schmid, Maximilian Waldner, Elisabeth Naschberger, Michael Scharl, Werner Müller, Claudia Günther, Christoph Becker, Michael Stürzl, Philipp Tripal
The aberrant regulation of the epithelial barrier integrity is involved in many diseases of the digestive tract, including inflammatory bowel diseases and colorectal cancer. Intestinal epithelial cell organoid cultures provide new perspectives for analyses of the intestinal barrier in vitro. However, established methods of barrier function analyses from two dimensional cultures have to be adjusted to the analysis of three dimensional organoid structures. Here we describe the methodology for analysis of epithelial barrier function and molecular regulation in intestinal organoids...
February 7, 2019: Stem Cell Research
Renée R C E Schreurs, Martin E Baumdick, Adrian F Sagebiel, Max Kaufmann, Michal Mokry, Paul L Klarenbeek, Nicola Schaltenberg, Fenja L Steinert, Jorik M van Rijn, Agata Drewniak, Sarah-May M L The, Roel Bakx, Joep P M Derikx, Niek de Vries, Willemijn E Corpeleijn, Steven T Pals, Nicola Gagliani, Manuel A Friese, Sabine Middendorp, Edward E S Nieuwenhuis, Konrad Reinshagen, Teunis B H Geijtenbeek, Johannes B van Goudoever, Madeleine J Bunders
Although the fetal immune system is considered tolerogenic, preterm infants can suffer from severe intestinal inflammation, including necrotizing enterocolitis (NEC). Here, we demonstrate that human fetal intestines predominantly contain tumor necrosis factor-α (TNF-α)+ CD4+ CD69+ T effector memory (Tem) cells. Single-cell RNA sequencing of fetal intestinal CD4+ T cells showed a T helper 1 phenotype and expression of genes mediating epithelial growth and cell cycling. Organoid co-cultures revealed a dose-dependent, TNF-α-mediated effect of fetal intestinal CD4+ T cells on intestinal stem cell (ISC) development, in which low T cell numbers supported epithelial development, whereas high numbers abrogated ISC proliferation...
February 5, 2019: Immunity
Yong Tao, Byunghak Kang, Daniel A Petkovich, Yuba R Bhandari, Julie In, Genevieve Stein-O'Brien, Xiangqian Kong, Wenbing Xie, Nicholas Zachos, Shinji Maegawa, Himani Vaidya, Stephen Brown, Ray-Whay Chiu Yen, Xiaojian Shao, Jai Thakor, Zhihao Lu, Yi Cai, Yuezheng Zhang, Izaskun Mallona, Miguel Angel Peinado, Cynthia A Zahnow, Nita Ahuja, Elana Fertig, Jean-Pierre Issa, Stephen B Baylin, Hariharan Easwaran
We addressed the precursor role of aging-like spontaneous promoter DNA hypermethylation in initiating tumorigenesis. Using mouse colon-derived organoids, we show that promoter hypermethylation spontaneously arises in cells mimicking the human aging-like phenotype. The silenced genes activate the Wnt pathway, causing a stem-like state and differentiation defects. These changes render aged organoids profoundly more sensitive than young ones to transformation by BrafV600E , producing the typical human proximal BRAFV600E -driven colon adenocarcinomas characterized by extensive, abnormal gene-promoter CpG-island methylation, or the methylator phenotype (CIMP)...
February 11, 2019: Cancer Cell
Ana D Mandić, Anni Woting, Tina Jaenicke, Anika Sander, Wiebke Sabrowski, Ulrike Rolle-Kampcyk, Martin von Bergen, Michael Blaut
Peripheral serotonin (5-hydroxytryptamine: 5-HT) synthesized in the intestine by enterochromaffin cells (ECs), plays an important role in the regulation of peristaltic of the gut, epithelial secretion and promotes the development and maintenance of the enteric neurons. Recent studies showed that the indigenous gut microbiota modulates 5-HT signalling and that ECs use sensory receptors to detect dietary and microbiota-derived signals from the lumen to subsequently transduce the information to the nervous system...
February 4, 2019: Scientific Reports
Zeynep Kabakci, Simon Käppeli, Claudio Cantù, Lasse D Jensen, Christiane König, Janine Toggweiler, Christian Gentili, Giovanni Ribaudo, Giuseppe Zagotto, Konrad Basler, Lorenzo A Pinna, Giorgio Cozza, Stefano Ferrari
CDC25 phosphatases play a key role in cell cycle transitions and are important targets for cancer therapy. Here, we set out to discover novel CDC25 inhibitors. Using a combination of computational methods, we defined a minimal common pharmacophore in established CDC25 inhibitors and performed virtual screening of a proprietary library. Based on the availability of crystal structures for CDC25A and CDC25B, we implemented a molecular docking strategy and carried out hit expansion/optimization. Enzymatic assays revealed that naphthoquinone scaffolds were the most promising CDC25 inhibitors among selected hits...
February 4, 2019: Scientific Reports
Helmuth Gehart, Johan H van Es, Karien Hamer, Joep Beumer, Kai Kretzschmar, Johanna F Dekkers, Anne Rios, Hans Clevers
Homeostatic regulation of the intestinal enteroendocrine lineage hierarchy is a poorly understood process. We resolved transcriptional changes during enteroendocrine differentiation in real time at single-cell level using a novel knockin allele of Neurog3, the master regulator gene briefly expressed at the onset of enteroendocrine specification. A bi-fluorescent reporter, Neurog3Chrono, measures time from the onset of enteroendocrine differentiation and enables precise positioning of single-cell transcriptomes along an absolute time axis...
January 25, 2019: Cell
Judith Kraiczy, Alexander D B Ross, Jessica L Forbester, Gordon Dougan, Ludovic Vallier, Matthias Zilbauer
No abstract text is available yet for this article.
October 23, 2018: Cellular and Molecular Gastroenterology and Hepatology
Kumar S Bishnupuri, David M Alvarado, Alexander N Khouri, Mark Shabsovich, Baosheng Chen, Brian K Dieckgraefe, Matthew A Ciorba
The tryptophan-metabolizing enzyme indoleamine 2,3 dioxygenase 1 (IDO1) is frequently overexpressed in epithelial-derived malignancies, where it plays a recognized role in promoting tumor immune tolerance. We previously demonstrated that the IDO1-kynurenine pathway (KP) also directly supports colorectal cancer (CRC) growth by promoting activation of β-catenin and driving neoplastic growth in mice lacking intact adaptive immunity. In this study, we sought to delineate the specific role of epithelial IDO1 in colon tumorigenesis and define how IDO1 and KP metabolites interact with pivotal neoplastic signaling pathways of the colon epithelium...
January 24, 2019: Cancer Research
Yi Liu, Yasunori Deguchi, Rui Tian, Daoyan Wei, Ling Wu, Weidong Chen, Weiguo Xu, Min Xu, Fuyao Liu, Shen Gao, Jonathan C Jaoude, Sarah P Chrieki, Micheline J Moussalli, Mihai Gagea, Jeffrey Morris, Russell R Broaddus, Xiangsheng Zuo, Imad Shureiqi
APC mutations activate aberrant β-catenin signaling to drive initiation of colorectal cancer (CRC), however, CRC progression requires additional molecular mechanisms. PPAR-delta (PPARD), a downstream target of β-catenin, is upregulated in CRC. However, promotion of intestinal tumorigenesis following deletion of PPARD in Apcmin mice has raised questions about the effects of PPARD on aberrant β-catenin activation and CRC. In this study, we used mouse models of PPARD overexpression or deletion combined with APC mutation (ApcΔ580) in intestinal epithelial cells (IEC) to elucidate the contributions of PPARD in CRC...
January 24, 2019: Cancer Research
Nicola Fenderico, Revina C van Scherpenzeel, Michael Goldflam, Davide Proverbio, Ingrid Jordens, Tomica Kralj, Sarah Stryeck, Tarek Z Bass, Guy Hermans, Christopher Ullman, Teodor Aastrup, Piet Gros, Madelon M Maurice
Wnt-induced β-catenin-mediated transcription is a driving force for stem cell self-renewal during adult tissue homeostasis. Enhanced Wnt receptor expression due to mutational inactivation of the ubiquitin ligases RNF43/ZNRF3 recently emerged as a leading cause for cancer development. Consequently, targeting canonical Wnt receptors such as LRP5/6 holds great promise for treatment of such cancer subsets. Here, we employ CIS display technology to identify single-domain antibody fragments (VHH) that bind the LRP6 P3E3P4E4 region with nanomolar affinity and strongly inhibit Wnt3/3a-induced β-catenin-mediated transcription in cells, while leaving Wnt1 responses unaffected...
January 21, 2019: Nature Communications
Faisal Minshawi, Mike R H White, Werner Muller, Neil Humphreys, Dean Jackson, Barry J Campbell, Antony Adamson, Stamatia Papoutsopoulou
Tumour necrosis factor (TNF) is a key cytokine during inflammatory responses and its dysregulation is detrimental in many inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease. Here, we used a bacterial artificial chromosome (BAC) construct that expresses luciferase under the control of the human TNF locus to generate a novel transgenic mouse, the hTNF.LucBAC strain. In vitro stimulation of hTNF.LucBAC cells of different origin revealed a cell specific response to stimuli demonstrating the integrated construct's ability as a proxy for inflammatory gene response...
January 17, 2019: Scientific Reports
Antonio V Alves da Silva, Stephanie B de Castro Oliveira, Sara C Di Rienzi, Kathleen Brown-Steinke, Lauren M Dehan, Jill K Rood, Vinicius S Carreira, Hung Le, Elizabeth A Maier, Kristina J Betz, Eitaro Aihara, Ruth E Ley, Geoffrey A Preidis, Lanlan Shen, Sean R Moore
Background: Folate and choline are essential methyl donor nutrients throughout the life span; however, the adverse effects of combined deficiency on early growth, intestinal epithelial morphology, and the gut microbiome remain only partially understood. Objectives: We investigated the effects of dietary folate and choline deficiency on early growth, small intestinal (SI) epithelial architecture, and the gut microbiota of mice. To explore potential mechanisms for adverse effects on gut epithelial morphology, we also evaluated gene expression and DNA methylation in mouse intestinal epithelial organoids (enteroids) maintained in methyl donor-deficient (MDD) conditions...
January 2019: Current developments in nutrition
Nobuhiro Nakamoto, Nobuo Sasaki, Ryo Aoki, Kentaro Miyamoto, Wataru Suda, Toshiaki Teratani, Takahiro Suzuki, Yuzo Koda, Po-Sung Chu, Nobuhito Taniki, Akihiro Yamaguchi, Mitsuhiro Kanamori, Nobuhiko Kamada, Masahira Hattori, Hiroshi Ashida, Michiie Sakamoto, Koji Atarashi, Seiko Narushima, Akihiko Yoshimura, Kenya Honda, Toshiro Sato, Takanori Kanai
Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease and its frequent complication with ulcerative colitis highlights the pathogenic role of epithelial barrier dysfunction. Intestinal barrier dysfunction has been implicated in the pathogenesis of PSC, yet its underlying mechanism remains unknown. Here, we identify Klebsiella pneumonia in the microbiota of patients with PSC and demonstrate that K. pneumoniae disrupts the epithelial barrier to initiate bacterial translocation and liver inflammatory responses...
January 14, 2019: Nature Microbiology
Yoshiaki Maru, Kunishige Onuma, Masako Ochiai, Toshio Imai, Yoshitaka Hippo
Inactivation of the Adenomatous Polyposis Coli (APC) gene is an initiating and the most relevant event in the majority of sporadic cases with colorectal cancer, providing a rationale for using Apc-mutant mice as the disease model. Whereas carcinogenesis has been observed only at the organism level, the recent development of organoid culture technique has enabled long-term propagation of intestinal stem cells in a physiological setting, raising the possibility that organoids could serve as an alternative platform for modeling colon carcinogenesis...
January 13, 2019: Cancer Science
Diksha Haksar, Eyleen de Poel, Linda H C Quarles van Ufford, Sumati Bhatia, Rainer Haag, Jeffrey M Beekman, Roland J Pieters
Cholera is a potentially fatal bacterial infection that affects a large number of people in the developing countries. It is caused by the cholera toxin (CT), an AB5 toxin secreted by Vibrio cholera. The toxin comprises of a toxic A-subunit and a pentameric B-subunit that binds to the intestinal cell surface. Several monovalent and multivalent inhibitors of the toxin have been synthesized but are too complicated and expensive for practical use in developing countries. Meta-nitrophenyl α-galactoside (MNPG) is a known promising ligand for CT and here mono- and multivalent compounds based on MNPG were synthesized...
January 10, 2019: Bioconjugate Chemistry
Makiko Kawaguchi, Koji Yamamoto, Naoki Takeda, Tsuyoshi Fukushima, Fumiki Yamashita, Katsuaki Sato, Kenichiro Kitamura, Yoshitaka Hippo, James W Janetka, Hiroaki Kataoka
Mutations in SPINT2 encoding the epithelial serine protease inhibitor hepatocyte growth factor activator inhibitor-2 (HAI-2) are associated with congenital tufting enteropathy. However, the functions of HAI-2 in vivo are poorly understood. Here we used tamoxifen-induced Cre-LoxP recombination in mice to ablate Spint2 . Mice lacking Spint2 died within 6 days after initiating tamoxifen treatment and showed severe epithelial damage in the whole intestinal tracts, and, to a lesser extent, the extrahepatic bile duct...
2019: Communications biology
Dustin Flanagan, Nick Barker, Natasha S Di Costanzo, Elizabeth Anne Mason, Austin Gurney, Valerie S Meniel, Sarah Koushyar, Chloe R Austin, Helen B Pearson, Alex Boussioutas, Hans Clevers, Toby J Phesse, Elisabeth Vincan
A subset of gastric cancer (GC) patients have mutations in genes that participate in or regulate Wnt signaling at the level of ligand (Wnt) receptor (Fzd) binding. Moreover, increased Fzd expression is associated with poor clinical outcome. Despite these findings, there are no in vivo studies investigating the potential of targeting Wnt receptors for treating GC, and the specific Wnt receptor transmitting oncogenic Wnt signaling in GC is unknown. Here we use inhibitors of Wnt/Fzd (OMP-18R5/Vantictumab) and conditional gene deletion to test the therapeutic potential of targeting Wnt signaling in preclinical models of intestinal-type gastric cancer and ex vivo organoid cultures...
January 8, 2019: Cancer Research
Meghan M Capeling, Michael Czerwinski, Sha Huang, Yu-Hwai Tsai, Angeline Wu, Melinda S Nagy, Benjamin Juliar, Nambirajan Sundaram, Yang Song, Woojin M Han, Shuichi Takayama, Eben Alsberg, Andres J Garcia, Michael Helmrath, Andrew J Putnam, Jason R Spence
Human intestinal organoids (HIOs) represent a powerful system to study human development and are promising candidates for clinical translation as drug-screening tools or engineered tissue. Experimental control and clinical use of HIOs is limited by growth in expensive and poorly defined tumor-cell-derived extracellular matrices, prompting investigation of synthetic ECM-mimetics for HIO culture. Since HIOs possess an inner epithelium and outer mesenchyme, we hypothesized that adhesive cues provided by the matrix may be dispensable for HIO culture...
December 19, 2018: Stem Cell Reports
Sara Rahmani, Natalia M Breyner, Hsuan-Ming Su, Elena F Verdu, Tohid F Didar
In recent years, the advent of intestinal organoid culture systems has revolutionized in vitro studies of the small intestine epithelium. Intestinal organoids are derived from self-organizing and self-renewing intestinal stem cells and closely recapitulate the native intestinal epithelium. They therefore represent a more physiologically-relevant in vitro model than conventional cell cultures for studying intestinal development, biology and pathophysiology. Moreover, they represent a promising and unprecedented new tool in the realm of regenerative and personalized medicine...
December 10, 2018: Biomaterials
Ryu Nishimura, Tomoaki Shirasaki, Kiichiro Tsuchiya, Yoshihide Miyake, Yusuke Watanabe, Shuji Hibiya, Sho Watanabe, Tetsuya Nakamura, Mamoru Watanabe
BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory disease of the colon with an intractable, recurrent course. The goal of UC therapy is to target mucosal healing because immune-suppressive therapy for UC frequently results in relapse. However, few drugs directly target mucosal healing. We, therefore, aim to evaluate the therapeutic effect of an investigational drug on intestinal epithelial cells in an in vitro UC model using human colonic organoids. METHODS: Colonic organoids were isolated from human colon and cultured...
January 1, 2019: Journal of Gastroenterology
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