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intestinal organoid

James R Bayrer, Hongtao Wang, Roy Nattiv, Miyuki Suzawa, Hazel S Escusa, Robert J Fletterick, Ophir D Klein, David D Moore, Holly A Ingraham
Epithelial dysfunction and crypt destruction are defining features of inflammatory bowel disease (IBD). However, current IBD therapies targeting epithelial dysfunction are lacking. The nuclear receptor LRH-1 (NR5A2) is expressed in intestinal epithelium and thought to contribute to epithelial renewal. Here we show that LRH-1 maintains intestinal epithelial health and protects against inflammatory damage. Knocking out LRH-1 in murine intestinal organoids reduces Notch signaling, increases crypt cell death, distorts the cellular composition of the epithelium, and weakens the epithelial barrier...
October 10, 2018: Nature Communications
Hao Zeng, Bo Lu, Raffaella Zamponi, Zinger Yang, Kristie Wetzel, Joseph Loureiro, Sina Mohammadi, Martin Beibel, Sebastian Bergling, John Reece-Hoyes, Carsten Russ, Guglielmo Roma, Jan S Tchorz, Paola Capodieci, Feng Cong
Wnt/β-catenin signaling plays pivotal roles in cell proliferation and tissue homeostasis by maintaining somatic stem cell functions. The mammalian target of rapamycin (mTOR) signaling functions as an integrative rheostat that orchestrates various cellular and metabolic activities that shape tissue homeostasis. Whether these two fundamental signaling pathways couple to exert physiological functions still remains mysterious. Using a genome-wide CRISPR-Cas9 screening, we discover that mTOR complex 1 (mTORC1) signaling suppresses canonical Wnt/β-catenin signaling...
October 8, 2018: Proceedings of the National Academy of Sciences of the United States of America
Yanchun Liu, Yijie Wang, Jason Chakroff, Jed Johnson, Aidan Farrell, Gail E Besner
OBJECTIVE: The objective of this study was to compare the impact of different ages of cell donors on the production of tissue engineered small intestine (TESI). METHODS: Four different ages of Lewis rats were chosen as donors of intestinal organoids: E18 fetuses, 5 day old newborns, 21 day old weanlings, and 6 week old adults. Harvested intestine was exposed to enzymatic digestion to release intestinal stem cell-containing organoids. Organoids were purified, concentrated, and seeded onto tubular polyglycolic acid (PGA) scaffolds...
October 4, 2018: Tissue Engineering. Part A
Tetsuya Nakamura
The intestinal epithelium not only acts as the physical structure that separates the intestinal lumen from the body but also actively participates in intestinal barrier functions. In the past decade, significant progress has been made in the development of culture technologies to maintain intestinal epithelial cells (IECs) as various forms of intestinal organoids. As these organoids allow for restoration of the physiological composition of IECs, they represent suitable models to study the mechanisms of development and differentiation or the molecular basis of functions in specific types of IECs, such as goblet cells, Paneth cells, tuft cells and M cells...
October 3, 2018: International Immunology
Konrad Aden, Kareen Bartsch, Joseph Dahl, Martin A M Reijns, Daniela Esser, Raheleh Sheibani-Tezerji, Anupam Sinha, Felix Wottawa, Go Ito, Neha Mishra, Katharina Knittler, Adam Burkholder, Lina Welz, Johan van Es, Florian Tran, Simone Lipinski, Nassim Kakavand, Christine Boeger, Ralph Lucius, Witigo von Schoenfels, Clemens Schafmayer, Lennart Lenk, Athena Chalaris, Hans Clevers, Christoph Röcken, Christoph Kaleta, Stefan Rose-John, Stefan Schreiber, Thomas Kunkel, Björn Rabe, Philip Rosenstiel
BACKGROUND & AIMS: RNase H2 is a holoenzyme comprising 3 subunits (ribonuclease H2 subunits A, B, and C) that cleaves RNA:DNA hybrids and removes misincorporated ribonucleotides from genomic DNA via ribonucleotide excision repair. Ribonucleotide incorporation by eukaryotic DNA polymerases occurs during every round of genome duplication and produces the most frequent type of naturally occurring DNA lesion. We investigated whether intestinal epithelial proliferation requires RNase H2 function and whether RNase H2 activity is disrupted during intestinal carcinogenesis...
September 28, 2018: Gastroenterology
Katia Beaudry, Marie-Josée Langlois, Amélie Montagne, Sébastien Cagnol, Julie C Carrier, Nathalie Rivard
The Ras/mitogen-activated protein kinase (MAPK) pathway controls fundamental cellular processes such as proliferation, differentiation, and apoptosis. The dual-specificity phosphatase 6 (DUSP6) regulates cytoplasmic MAPK signaling by dephosphorylating and inactivating extracellular signal-regulated kinase (ERK1/2) MAPK. To determine the role of DUSP6 in the maintenance of intestinal homeostasis, we characterized the intestinal epithelial phenotype of Dusp6 knockout (KO) mice under normal, oncogenic, and proinflammatory conditions...
October 1, 2018: Journal of Cellular Physiology
Bernhard J Mueller, Alexander V Zhdanov, Sergey M Borisov, Tara Foley, Irina A Okkelman, Vassiliy Tsytsarev, Qinggong Tang, Reha S Erzurumlu, Yu Chen, Haijiang Zhang, Claudio Toncelli, Ingo Klimant, Dmitri B Papkovsky, Ruslan I Dmitriev
The imaging of real-time fluxes of K+ ions in live cell with high dynamic range (5-150 mM) is of paramount importance for neuroscience and physiology of the gastrointestinal tract, kidney and other tissues. In particular, the research on high-performance deep-red fluorescent nanoparticle-based biosensors is highly anticipated. We found that BODIPY-based FI3 K+ -sensitive fluoroionophore encapsulated in cationic polymer RL100 nanoparticles displays unusually strong efficiency in staining of broad spectrum of cell models, such as primary neurons and intestinal organoids...
February 28, 2018: Advanced Functional Materials
Anna S Lehle, Henner F Farin, Benjamin Marquardt, Birgitta E Michels, Thomas Magg, Yue Li, Yanshan Liu, Maryam Ghalandary, Katja Lammens, Sebastian Hollizeck, Meino Rohlfs, Fabian Hauck, Raffaele Conca, Christoph Walz, Batia Weiss, Atar Lev, Amos J Simon, Olaf Groß, Moritz M Gaidt, Veit Hornung, Hans Clevers, Nadine Yazbeck, Rima Hanna-Wakim, Dror S Shouval, Neil Warner, Raz Somech, Aleixo M Muise, Scott S Snapper, Philip Bufler, Sibylle Koletzko, Christoph Klein, Daniel Kotlarz
Caspase-8 (CASP8) is a protease that initiates apoptosis and regulates inflammation and immune responses. We identified germline mutations in CASP8 in 3 unrelated patients with infant-onset inflammatory bowel disease: 2 patients were homozygous for the mutation 710A>G, p.Q237R, which resulted in reduced protein expression, and 1 patient carried the mutation 793C>T, p.R265W. We isolated peripheral blood mononuclear cells from our index patient and observed defects in T- and B-cell maturation, proliferation, and/or activation...
September 26, 2018: Gastroenterology
James Clinton, Penney McWilliams-Koeppen
Organoids are primary patient-derived micro tissues grown within a three-dimensional extracellular matrix that better represents in vivo physiology and genetic diversity than existing two-dimensional cell lines. Organoids rely on the self-renewal and differentiation of tissue-resident stem cells that expand in culture and self-organize into complex three-dimensional structures. Depending on the tissue, organoids typically lack stromal, vascular, neural, and immune cells but otherwise can contain cells from all the respective tissue-specific cell lineages found in vivo...
September 28, 2018: Current Protocols in Cell Biology
Neil O'Donnell, Irina A Okkelman, Peter Timashev, Tatyana I Gromovykh, Dmitri B Papkovsky, Ruslan I Dmitriev
Quantitative measurement of pH and metabolite gradients by microscopy is one of the challenges in the production of scaffold-grown organoids and multicellular aggregates. Herein, we used the cellulose-binding domain (CBD) of the Cellulomonas fimi CenA protein for designing biosensor scaffolds that allow measurement of pH and Ca2+ gradients by fluorescence intensity and lifetime imaging (FLIM) detection modes. By fusing CBD with pH-sensitive enhanced cyan fluorescent protein (CBD-ECFP), we achieved efficient labeling of cellulose-based scaffolds based on nanofibrillar, bacterial cellulose, and decellularized plant materials...
September 25, 2018: Acta Biomaterialia
Pan Ye, Y Jeffrey Chiang, Zhen Qi, Yehua Li, Shan Wang, Yuan Liu, Xintong Li, Ye-Guang Chen
Lgr5+ intestinal stem cells are crucial for fast homeostatic renewal of intestinal epithelium and Wnt/β-catenin signaling plays an essential role in this process by sustaining stem cell self-renewal. The poly(ADP-ribose) polymerases tankyrases (TNKSs) mediate protein poly-ADP-ribosylation and are involved in multiple cellular processes such as Wnt signaling regulation, mitotic progression and telomere maintenance. However, little is known about the physiological function of TNKSs in epithelium homeostasis regulation...
September 2018: PLoS Genetics
Hayley Derricott, Lisa Luu, Wai Yee Fong, Catherine S Hartley, Luke J Johnston, Stuart D Armstrong, Nadine Randle, Carrie A Duckworth, Barry J Campbell, Jonathan M Wastling, Janine L Coombes
The in vitro 3D culture of intestinal epithelium is a valuable resource in the study of its function. Organoid culture exploits stem cells' ability to regenerate and produce differentiated epithelium. Intestinal organoid models from rodent or human tissue are widely available whereas large animal models are not. Livestock enteric and zoonotic diseases elicit significant morbidity and mortality in animal and human populations. Therefore, livestock species-specific models may offer novel insights into host-pathogen interactions and disease responses...
September 26, 2018: Cell and Tissue Research
Konrad Aden, Florian Tran, Go Ito, Raheleh Sheibani-Tezerji, Simone Lipinski, Jan W Kuiper, Markus Tschurtschenthaler, Svetlana Saveljeva, Joya Bhattacharyya, Robert Häsler, Kareen Bartsch, Anne Luzius, Marlene Jentzsch, Maren Falk-Paulsen, Stephanie T Stengel, Lina Welz, Robin Schwarzer, Björn Rabe, Winfried Barchet, Stefan Krautwald, Gunther Hartmann, Manolis Pasparakis, Richard S Blumberg, Stefan Schreiber, Arthur Kaser, Philip Rosenstiel
A coding variant of the inflammatory bowel disease (IBD) risk gene ATG16L1 has been associated with defective autophagy and deregulation of endoplasmic reticulum (ER) function. IL-22 is a barrier protective cytokine by inducing regeneration and antimicrobial responses in the intestinal mucosa. We show that ATG16L1 critically orchestrates IL-22 signaling in the intestinal epithelium. IL-22 stimulation physiologically leads to transient ER stress and subsequent activation of STING-dependent type I interferon (IFN-I) signaling, which is augmented in Atg16l1 ΔIEC intestinal organoids...
September 25, 2018: Journal of Experimental Medicine
Ravinder Nagpal, Tiffany M Newman, Shaohua Wang, Shalini Jain, James F Lovato, Hariom Yadav
This study aimed to determine the association between non-high-fat diet-induced obesity- (non-DIO-) associated gut microbiome dysbiosis with gut abnormalities like cellular turnover of intestinal cells, tight junctions, and mucin formation that can impact gut permeability. We used leptin-deficient (Lepob/ob ) mice in comparison to C57BL/6J control mice, which are fed on identical diets, and performed comparative and correlative analyses of gut microbiome composition, gut permeability, intestinal structural changes, tight junction-mucin formation, cellular turnover, and stemness genes...
2018: Journal of Diabetes Research
Ellen E Higginson, Girish Ramachandran, Aruna Panda, Steven T Shipley, Edwin H Kriel, Louis J DeTolla, Michael Lipsky, Darren J Perkins, Rosangela Salerno-Goncalves, Marcelo B Sztein, Marcela F Pasetti, Myron M Levine, Sharon M Tennant
A notable proportion of Salmonella -associated gastroenteritis in the United States is attributed to Salmonella enterica serovar Typhimurium. We have previously shown that live-attenuated S. Typhimurium vaccine candidate CVD 1921 (I77 Δ guaBA Δ clpP ) was safe and immunogenic in rhesus macaques, but was shed for an undesirably long time post-immunization. In mice, occasional mortality post-vaccination was also noted (approximately 1 in every 15 mice). Herein we describe a further attenuated vaccine candidate strain harboring deletions in two additional genes, htrA and pipA We determined that S...
September 24, 2018: Infection and Immunity
Xiaogang Hou, David F Chang, Andrew Trecartin, Erik R Barthel, Christopher R Schlieve, Mark R Frey, Kathryn L Fowler, Tracy C Grikscheit
NEW FINDINGS: What is the central question of this study? Tissue-engineered small intestine (TESI) was previously generated in vivo by immediate implantation of organoid units (OU) derived from both mouse and human donor intestine. Although immediate transplantation of OU into patients shows promise as a potential future therapy, some critically ill patients may require delayed transplantation. What is the main finding and its importance? Unlike enteroids that consist of isolated intestinal crypts, short and long-term cultured organoid units are composed of epithelial and mesenchymal cells derived from mouse or human intestine...
September 19, 2018: Experimental Physiology
Yoshihiro Eriguchi, Kiminori Nakamura, Yuki Yokoi, Rina Sugimoto, Shuichiro Takahashi, Daigo Hashimoto, Takanori Teshima, Tokiyoshi Ayabe, Michael E Selsted, André J Ouellette
Paneth cells contribute to small intestinal homeostasis by secreting antimicrobial peptides and constituting the intestinal stem cell (ISC) niche. Certain T cell-mediated enteropathies are characterized by extensive Paneth cell depletion coincident with mucosal destruction and dysbiosis. In this study, mechanisms of intestinal crypt injury have been investigated by characterizing responses of mouse intestinal organoids (enteroids) in coculture with mouse T lymphocytes. Activated T cells induced enteroid damage, reduced Paneth cell and Lgr5+ ISC mRNA levels, and induced Paneth cell death through a caspase-3/7-dependent mechanism...
September 20, 2018: JCI Insight
Jooske F van Lidth de Jeude, Claudia N Spaan, Bartolomeus J Meijer, Wouter L Smit, Tanya Td Soeratram, Mattheus C B Wielenga, B Florien Westendorp, Amy S Lee, Sander Meisner, Jacqueline Lm Vermeulen, Manon E Wildenberg, Gijs R van den Brink, Vanesa Muncan, Jarom Heijmans
Deletion of endoplasmic reticulum (ER) resident chaperone Grp78 results in activation of the unfolded protein response and causes rapid depletion of the entire intestinal epithelium. Whether modest reduction of Grp78 may affect stem cell fate without compromising intestinal integrity remains unknown. Here we employ a model of epithelial-specific, heterozygous Grp78 deletion by use of VillinCreERT2-Rosa26ZsGreen/LacZ-Grp78+/fl mice and organoids. We examine models of irradiation and tumorigenesis both in vitro and in vivo...
September 19, 2018: Cancer Research
Jessica L Forbester, Emily A Lees, David Goulding, Sally Forrest, Amy Yeung, Anneliese Speak, Simon Clare, Eve L Coomber, Subhankar Mukhopadhyay, Judith Kraiczy, Fernanda Schreiber, Trevor D Lawley, Robert E W Hancock, Holm H Uhlig, Matthias Zilbauer, Fiona Powrie, Gordon Dougan
Intestinal epithelial cells (IECs) play a key role in regulating immune responses and controlling infection. However, the direct role of IECs in restricting pathogens remains incompletely understood. Here, we provide evidence that IL-22 primed intestinal organoids derived from healthy human induced pluripotent stem cells (hIPSCs) to restrict Salmonella enterica serovar Typhimurium SL1344 infection. A combination of transcriptomics, bacterial invasion assays, and imaging suggests that IL-22-induced antimicrobial activity is driven by increased phagolysosomal fusion in IL-22-pretreated cells...
October 2, 2018: Proceedings of the National Academy of Sciences of the United States of America
Ricard Garcia-Carbonell, Jerry Wong, Ju Youn Kim, Lisa Abernathy Close, Brigid S Boland, Thomas L Wong, Philip A Harris, Samuel B Ho, Soumita Das, Peter B Ernst, Roman Sasik, William J Sandborn, John Bertin, Pete J Gough, John T Chang, Michelle Kelliher, David Boone, Monica Guma, Michael Karin
Intestinal epithelial cell (IEC) death is a common feature of inflammatory bowel disease (IBD) that triggers inflammation by compromising barrier integrity. In many patients with IBD, epithelial damage and inflammation are TNF-dependent. Elevated TNF production in IBD is accompanied by increased expression of the TNFAIP3 gene, which encodes A20, a negative feedback regulator of NF-κB. A20 in intestinal epithelium from patients with IBD coincided with the presence of cleaved caspase-3, and A20 transgenic (Tg) mice, in which A20 is expressed from an IEC-specific promoter, were highly susceptible to TNF-induced IEC death, intestinal damage, and shock...
September 25, 2018: Proceedings of the National Academy of Sciences of the United States of America
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