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Gut organoid

Andrew Leber, Raquel Hontecillas, Nuria Tubau-Juni, Victoria Zoccoli-Rodriguez, Vida Abedi, Josep Bassaganya-Riera
Interactions among the gut microbiome, dysregulated immune responses, and genetic factors contribute to the pathogenesis of inflammatory bowel disease (IBD). Nlrx1 -/- mice have exacerbated disease severity, colonic lesions, and increased inflammatory markers. Global transcriptomic analyses demonstrate enhanced mucosal antimicrobial defense response, chemokine and cytokine expression, and epithelial cell metabolism in colitic Nlrx1 -/- mice compared to wild-type (WT) mice. Cell-specificity studies using cre-lox mice demonstrate that the loss of NLRX1 in intestinal epithelial cells (IEC) recapitulate the increased sensitivity to DSS colitis observed in whole body Nlrx1 -/- mice...
2018: Frontiers in Immunology
Sarah N Boers, Karin M de Winter-de Groot, Jacquelien Noordhoek, Vincent Gulmans, Cornelis K van der Ent, Johannes J M van Delden, Annelien L Bredenoord
BACKGROUND: Organoid technology enables the cultivation of human tissues in a dish. Its precision medicine potential could revolutionize the Cystic Fibrosis (CF) field. We provide a first thematic exploration of the patient perspective on organoid technology to set the further research agenda, which is necessary for responsible development of this ethically challenging technology. METHODS: 23 semi-structured qualitative interviews with 14 Dutch adult CF patients and 12 parents of young CF patients to examine their experiences, opinions, and attitudes regarding organoid technology...
March 6, 2018: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
Carly Leung, Si Hui Tan, Nick Barker
The discovery of leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) as both a marker of adult stem cells and a critical modulator of their activity via its role as an effector of Wnt/R-spondin (Rspo) signaling has driven major advances in our understanding of stem cell biology during homeostasis, regeneration, and disease. Exciting new mouse and organoid culture models developed to study the endogenous behavior of Lgr5-expressing cells in health and disease settings have revealed the existence of facultative stem cell populations responsible for tissue regeneration, cancer stem cells (CSCs) driving metastasis in the gut, and Lgr5+ niche cells in the lung...
February 21, 2018: Trends in Cell Biology
Ran-Ran Zhang, Masaru Koido, Tomomi Tadokoro, Rie Ouchi, Tatsuya Matsuno, Yasuharu Ueno, Keisuke Sekine, Takanori Takebe, Hideki Taniguchi
Early endoderm progenitors naturally possess robust propagating potential to develop a majority of meter-long gastrointestinal tracts and are therefore considered as a promising source for therapy. Here, we demonstrated the reproducible generation of human CDX2 + posterior gut endoderm cells (PGECs) from five induced pluripotent stem cell clones by manipulating FGF, TGF, and WNT signaling. Transcriptome analysis suggested that putative PGECs harbored an intermediate signature profile between definitive endoderm and organ-specific endoderm...
February 1, 2018: Stem Cell Reports
Ramon M Eichenberger, Md Hasanuzzaman Talukder, Matthew A Field, Phurpa Wangchuk, Paul Giacomin, Alex Loukas, Javier Sotillo
Whipworms are parasitic nematodes that live in the gut of more than 500 million people worldwide. Owing to the difficulty in obtaining parasite material, the mouse whipworm Trichuris muris has been extensively used as a model to study human whipworm infections. These nematodes secrete a multitude of compounds that interact with host tissues where they orchestrate a parasitic existence. Herein we provide the first comprehensive characterization of the excretory/secretory products of T. muris. We identify 148 proteins secreted by T...
2018: Journal of Extracellular Vesicles
Malgorzata Panek, Maja Grabacka, Malgorzata Pierzchalska
Recently organoids have become widely used in vitro models of many tissue and organs. These type of structures, originated from embryonic or adult mammalian intestines, are called "mini guts". They organize spontaneously when intestinal crypts or stem cells are embedded in the extracellular matrix proteins preparation scaffold (Matrigel). This approach has some disadvantages, as Matrigel is undefined (the concentrations of growth factors and other biologically active components in it may vary from batch to batch), difficult to handle and expensive...
January 25, 2018: Cytotechnology
Jonathan P Mochel, Albert E Jergens, Dawn Kingsbury, Hyun Jung Kim, Martín G Martín, Karin Allenspach
Recent advances in our understanding of the intestinal stem cell niche and the role of key signaling pathways on cell growth and maintenance have allowed the development of fully differentiated epithelial cells in 3D organoids. Stem cell-derived organoids carry significant levels of proteins that are natively expressed in the gut and have important roles in drug transport and metabolism. They are, therefore, particularly relevant to study the gastrointestinal (GI) absorption of oral medications. In addition, organoids have the potential to serve as a robust preclinical model for demonstrating the effectiveness of new drugs more rapidly, with more certainty, and at lower costs compared with live animal studies...
December 12, 2017: AAPS Journal
Yu Takahashi, Shintaro Sato, Yosuke Kurashima, Tomohisa Yamamoto, Shiho Kurokawa, Yoshikazu Yuki, Naoki Takemura, Satoshi Uematsu, Chen-Yi Lai, Makoto Otsu, Hiroshi Matsuno, Hideki Osawa, Tsunekazu Mizushima, Junichi Nishimura, Mikio Hayashi, Takayuki Yamaguchi, Hiroshi Kiyono
Gut epithelial organoids are routinely used to investigate intestinal biology; however, current culture methods are not amenable to genetic manipulation, and it is difficult to generate sufficient numbers for high-throughput studies. Here, we present an improved culture system of human induced pluripotent stem cell (iPSC)-derived intestinal organoids involving four methodological advances. (1) We adopted a lentiviral vector to readily establish and optimize conditioned medium for human intestinal organoid culture...
January 9, 2018: Stem Cell Reports
Adam L Haber, Moshe Biton, Noga Rogel, Rebecca H Herbst, Karthik Shekhar, Christopher Smillie, Grace Burgin, Toni M Delorey, Michael R Howitt, Yarden Katz, Itay Tirosh, Semir Beyaz, Danielle Dionne, Mei Zhang, Raktima Raychowdhury, Wendy S Garrett, Orit Rozenblatt-Rosen, Hai Ning Shi, Omer Yilmaz, Ramnik J Xavier, Aviv Regev
Intestinal epithelial cells absorb nutrients, respond to microbes, function as a barrier and help to coordinate immune responses. Here we report profiling of 53,193 individual epithelial cells from the small intestine and organoids of mice, which enabled the identification and characterization of previously unknown subtypes of intestinal epithelial cell and their gene signatures. We found unexpected diversity in hormone-secreting enteroendocrine cells and constructed the taxonomy of newly identified subtypes, and distinguished between two subtypes of tuft cell, one of which expresses the epithelial cytokine Tslp and the pan-immune marker CD45, which was not previously associated with non-haematopoietic cells...
November 16, 2017: Nature
Judith Kraiczy, Komal M Nayak, Kate J Howell, Alexander Ross, Jessica Forbester, Camilla Salvestrini, Roxana Mustata, Sally Perkins, Amanda Andersson-Rolf, Esther Leenen, Anke Liebert, Ludovic Vallier, Philip C Rosenstiel, Oliver Stegle, Gordon Dougan, Robert Heuschkel, Bon-Kyoung Koo, Matthias Zilbauer
OBJECTIVE: Human intestinal epithelial organoids (IEOs) are increasingly being recognised as a highly promising translational research tool. However, our understanding of their epigenetic molecular characteristics and behaviour in culture remains limited. DESIGN: We performed genome-wide DNA methylation and transcriptomic profiling of human IEOs derived from paediatric/adult and fetal small and large bowel as well as matching purified human gut epithelium. Furthermore, organoids were subjected to in vitro differentiation and genome editing using CRISPR/Cas9 technology...
November 15, 2017: Gut
Zhixiang Tong, Keir Martyn, Andy Yang, Xiaolei Yin, Benjamin E Mead, Nitin Joshi, Nicholas E Sherman, Robert S Langer, Jeffrey M Karp
Current ISC culture systems face significant challenges such as animal-derived or undefined matrix compositions, batch-to-batch variability (e.g. Matrigel-based organoid culture), and complexity of assaying cell aggregates such as organoids which renders the research and clinical translation of ISCs challenging. Here, through screening for suitable ECM components, we report a defined, collagen based monolayer culture system that supports the growth of mouse and human intestinal epithelial cells (IECs) enriched for an Lgr5(+) population comparable or higher to the levels found in a standard Matrigel-based organoid culture...
October 26, 2017: Biomaterials
Kate Joanne Howell, Judith Kraiczy, Komal M Nayak, Marco Gasparetto, Alexander Ross, Claire Lee, Tim N Mak, Bon-Kyoung Koo, Nitin Kumar, Trevor Lawley, Anupam Sinha, Philip Rosenstiel, Robert Heuschkel, Oliver Stegle, Matthias Zilbauer
BACKGROUND & AIMS: We analyzed DNA methylation patterns and transcriptomes of primary intestinal epithelial cells (IEC) of children newly diagnosed with inflammatory bowel diseases (IBD) to learn more about pathogenesis. METHODS: We obtained mucosal biopsies (n = 236) collected from terminal ileum and ascending and sigmoid colons of children (median age, 13 years) newly diagnosed with IBD (43 with Crohn's disease [CD], 23 with ulcerative colitis), and 30 children without IBD (controls)...
October 12, 2017: Gastroenterology
Angela Nakauka-Ddamba, Christopher J Lengner
Intestinal organoids offer great promise for modeling intestinal diseases; however, harvesting intestinal tissue is invasive and directed hPSC differentiation protocols are laborious and costly. In this issue of Cell Stem Cell, Miura and Suzuki (2017) describe the direct conversion of somatic cells from both mice and humans into robust intestinal epithelial tissue.
October 5, 2017: Cell Stem Cell
Yeojung Kim, Gail A West, Greeshma Ray, Sean P Kessler, Aaron C Petrey, Claudio Fiocchi, Christine McDonald, Michelle S Longworth, Laura E Nagy, Carol A de la Motte
Tight junction proteins are critical in maintaining homeostatic intestinal permeability. Multiple intestinal inflammatory diseases are correlated with reduced expression of tight junction proteins. We have recently reported that oral treatment of mice with Hyaluronan 35kDa (HA35) increases colonic expression of tight junction protein zonula occludens-1 (ZO-1). Here, we investigate whether HA35 treatment enhances ZO-1 expression by direct interaction with intestinal epithelium in vitro and have identified the HA receptor responsible for HA35-mediated ZO-1 induction in colonic epithelium in vitro and in vivo...
October 1, 2017: Matrix Biology: Journal of the International Society for Matrix Biology
Dongsheng Zhang, Ming Tan, Weiming Zhong, Ming Xia, Pengwei Huang, Xi Jiang
Through pluripotent stem cell (PSC) technology, human intestinal organoids (HIOs) with remarkably similarity to the fetal intestine in cellular composition, architecture, and absorptive/secretory functions have been successfully developed, providing a useful in vitro model system to study the structure and function of human congenital gut and intestinally related diseases. We report here the usefulness of HIOs as a model system to study intestinal carbohydrate expression, virus-host interaction, and replication of human noroviruses (huNoVs)...
October 3, 2017: Scientific Reports
Yael Morgenstern, Upasana Das Adhikari, Muneef Ayyash, Ela Elyada, Beáta Tóth, Andreas Moor, Shalev Itzkovitz, Yinon Ben-Neriah
The intestinal epithelium holds an immense regenerative capacity mobilized by intestinal stem cells (ISCs), much of it supported by Wnt pathway activation. Several unique regulatory mechanisms ensuring optimal levels of Wnt signaling have been recognized in ISCs. Here, we identify another Wnt signaling amplifier, CKIε, which is specifically upregulated in ISCs and is essential for ISC maintenance, especially in the absence of its close isoform CKIδ. Co-ablation of CKIδ/ε in the mouse gut epithelium results in rapid ISC elimination, with subsequent growth arrest, crypt-villous shrinking, and rapid mouse death...
October 16, 2017: EMBO Journal
Jerry Zhou, Michael D O'Connor, Vincent Ho
Effective digestion requires propagation of food along the entire length of the gastrointestinal tract. This process involves coordinated waves of peristalsis produced by enteric neural cell types, including different categories of interstitial cells of Cajal (ICC). Impaired food transport along the gastrointestinal tract, either too fast or too slow, causes a range of gut motility disorders that affect millions of people worldwide. Notably, loss of ICC has been shown to affect gut motility. Patients that suffer from gut motility disorders regularly experience diarrhoea and/or constipation, insomnia, anxiety, attention lapses, irritability, dizziness, and headaches that greatly affect both physical and mental health...
September 26, 2017: International Journal of Molecular Sciences
Runping Liu, Xiaojiaoyang Li, Zhiming Huang, Derrick Zhao, Bhagyalaxmi Sukka Ganesh, Guanhua Lai, William M Pandak, Phillip B Hylemon, Jasmohan S Bajaj, Arun J Sanyal, Huiping Zhou
Impaired intestinal barrier function promotes the progression of various liver diseases including cholestatic liver disease. The close association of primary sclerosing cholangitis (PSC) with inflammatory bowel disease highlights the importance of the gut-liver axis. It has been reported that bile duct ligation (BDL)-induced liver fibrosis is significantly reduced in C/EBP homologous protein knock out (CHOP(-/-) ) mice. However, the underlying mechanisms remain unclear. In the current study, we demonstrate that BDL induces striking and acute hepatic ER stress responses after 1 day, which return to normal after 3 days...
September 19, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Daniel Perea, Jordi Guiu, Bruno Hudry, Chrysoula Konstantinidou, Alexandra Milona, Dafni Hadjieconomou, Thomas Carroll, Nina Hoyer, Dipa Natarajan, Jukka Kallijärvi, James A Walker, Peter Soba, Nikhil Thapar, Alan J Burns, Kim B Jensen, Irene Miguel-Aliaga
Expression of the Ret receptor tyrosine kinase is a defining feature of enteric neurons. Its importance is underscored by the effects of its mutation in Hirschsprung disease, leading to absence of gut innervation and severe gastrointestinal symptoms. We report a new and physiologically significant site of Ret expression in the intestine: the intestinal epithelium. Experiments in Drosophila indicate that Ret is expressed both by enteric neurons and adult intestinal epithelial progenitors, which require Ret to sustain their proliferation...
October 16, 2017: EMBO Journal
K B Uldahl, S T Walk, S C Olshefsky, M J Young, X Peng
AIMS: Analysis of the stability and safety of Sulfolobus monocaudavirus 1 (SMV1) during passage through the mammalian GI tract. METHODS AND RESULTS: A major challenge of using nano-vectors to target gut microbiome is their survival during passage through the extremely acidic and proteolytic environment of the mammalian GI tract. Here, we investigated the thermo-acidophilic archaeal virus SMV1 as a candidate therapeutic nano-vector for the distal mammalian GI tract microbiome...
September 11, 2017: Journal of Applied Microbiology
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