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https://www.readbyqxmd.com/read/28078320/lgr4-and-lgr5-function-redundantly-during-human-endoderm-differentiation
#1
Yu-Hwai Tsai, David R Hill, Namit Kumar, Sha Huang, Alana M Chin, Briana R Dye, Melinda S Nagy, Michael P Verzi, Jason R Spence
BACKGROUND & AIMS: The Lgr family of transmembrane proteins (Lgr4, 5, 6) act as functional receptors for R-spondin proteins (Rspo 1, 2, 3, 4), and potentiate Wnt signaling in different contexts. Lgr5 is arguably the best characterized of the Lgr family members in a number of adult and embryonic contexts in mice. However, the function of LGR family members in early embryonic development is unclear, and has not been explored during human development or tissue differentiation in detail. METHODS: We interrogated the function and expression of LGR family members using human pluripotent stem cell-derived tissues including definitive endoderm, mid/hindgut, and intestinal organoids...
September 2016: Cellular and Molecular Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/28074039/cd34-mesenchymal-cells-are-a-major-component-of-the-intestinal-stem-cells-niche-at-homeostasis-and-after-injury
#2
Igor Stzepourginski, Giulia Nigro, Jean-Marie Jacob, Sophie Dulauroy, Philippe J Sansonetti, Gérard Eberl, Lucie Peduto
The intestinal epithelium is continuously renewed by intestinal epithelial stem cells (IESCs) positioned at the base of each crypt. Mesenchymal-derived factors are essential to maintain IESCs; however, the cellular composition and development of such mesenchymal niche remains unclear. Here, we identify pericryptal CD34(+) Gp38(+) αSMA(-) mesenchymal cells closely associated with Lgr5(+) IESCs. We demonstrate that CD34(+) Gp38(+) cells are the major intestinal producers of the niche factors Wnt2b, Gremlin1, and R-spondin1, and are sufficient to promote maintenance of Lgr5(+) IESCs in intestinal organoids, an effect mainly mediated by Gremlin1...
January 10, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28072391/braf-v600e-cooperates-with-cdx2-inactivation-to-promote-serrated-colorectal-tumorigenesis
#3
Naoya Sakamoto, Ying Feng, Carmine Stolfi, Yuki Kurosu, Maranne Green, Jeffry Lin, Megan Green, Kazuhiro Sentani, Wataru Yasui, Martin McMahon, Karin M Hardiman, Jason R Spence, Nobukatsu Horita, Joel K Greenson, Rork Kuick, Kathy R Cho, Eric R Fearon
While 20-30% of colorectal cancers (CRCs) may arise from precursors with serrated glands, only 8-10% of CRCs manifest serrated morphology at diagnosis. Markers for distinguishing CRCs arising from 'serrated' versus 'conventional adenoma' precursors are lacking. We studied 36 human serrated CRCs and found CDX2 loss or BRAF mutations in ~60% of cases and often together (p= .04). CDX2(Null)/BRAF(V600E) expression in adult mouse intestinal epithelium led to serrated morphology tumors (including carcinomas) and BRAF(V600E) potently interacted with CDX2 silencing to alter gene expression...
January 10, 2017: ELife
https://www.readbyqxmd.com/read/28061355/hacking-the-matrix
#4
Michael Czerwinski, Jason R Spence
Recently in Nature, Gjorevski et al. (2016) describe a fully defined synthetic hydrogel that mimics the extracellular matrix to support in vitro growth of intestinal stem cells and organoids. The hydrogel allows exquisite control over the chemical and physical in vitro niche and enables identification of regulatory properties of the matrix.
January 5, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28061353/created-of-warm-blood-and-nerves-restoring-an-enteric-nervous-system-in-organoids
#5
Christopher R Schlieve, Tracy C Grikscheit
The enteric nervous system (ENS) regulates numerous gastrointestinal functions, including epithelial barrier permeability and motility. In a recent Nature Medicine study, Workman et al. (2016) propose a method for introducing human pluripotent stem cell-derived enteric neural crest cells into developing human intestinal organoids, thereby restoring ENS cell types and contractile function.
January 5, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/27983963/simultaneous-paralogue-knockout-using-a-crispr-concatemer-in-mouse-small-intestinal-organoids
#6
Amanda Andersson-Rolf, Alessandra Merenda, Roxana C Mustata, Taibo Li, Sabine Dietmann, Bon-Kyoung Koo
Approaches based on genetic modification have been invaluable for investigating a wide array of biological processes, with gain- and loss-of-function approaches frequently used to investigate gene function. However, the presence of paralogues, and hence possible genetic compensation, for many genes necessitates the knockout (KO) of all paralogous genes in order to observe clear phenotypic change. CRISPR technology, the most recently described tool for gene editing, can generate KOs with unprecedented ease and speed and has been used in adult stem cell-derived organoids for single gene knockout, gene knock-in and gene correction...
October 27, 2016: Developmental Biology
https://www.readbyqxmd.com/read/27979825/the-critical-role-of-microbiota-within-cecal-crypts-on-the-regenerative-capacity-of-the-intestinal-epithelium-following-surgical-stress
#7
Alexander Zaborin, Monika Krezalek, Sanjiv Hyoju, Jennifer R DeFazio, Namrata Setia, Natalia Belogortseva, Vytautas P Bindokas, Qiti Guo, Olga Zaborina, John C Alverdy
Cecal crypts represent a unique niche that are normally occupied by the commensal microbiota. Due to their density and close proximity to stem cells, microbiota within cecal crypts may modulate epithelial regeneration. Here it is demonstrated that surgical stress, a process that invariably involves a short period of starvation, antibiotic exposure and tissue injury, results in cecal crypt evacuation of their microbiota. Crypts devoid of their microbiota display pathophysiological features characterized by abnormal stem cell activation as judged by Lgr5 staining, abnormal stem cell distribution with cells migrating toward the tips of the crypts, and an increase in TUNEL positive cells...
December 15, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/27974209/tmem258-is-a-component-of-the-oligosaccharyltransferase-complex-controlling-er-stress-and-intestinal-inflammation
#8
Daniel B Graham, Ariel Lefkovith, Patrick Deelen, Niek de Klein, Mukund Varma, Angela Boroughs, A Nicole Desch, Aylwin C Y Ng, Gaelen Guzman, Monica Schenone, Christine P Petersen, Atul K Bhan, Manuel A Rivas, Mark J Daly, Steven A Carr, Cisca Wijmenga, Ramnik J Xavier
Significant insights into disease pathogenesis have been gleaned from population-level genetic studies; however, many loci associated with complex genetic disease contain numerous genes, and phenotypic associations cannot be assigned unequivocally. In particular, a gene-dense locus on chromosome 11 (61.5-61.65 Mb) has been associated with inflammatory bowel disease, rheumatoid arthritis, and coronary artery disease. Here, we identify TMEM258 within this locus as a central regulator of intestinal inflammation...
December 13, 2016: Cell Reports
https://www.readbyqxmd.com/read/27973570/use-of-fluorescence-lifetime-imaging-microscopy-flim-as-a-timer-of-cell-cycle-s-phase
#9
Irina A Okkelman, Ruslan I Dmitriev, Tara Foley, Dmitri B Papkovsky
Incorporation of thymidine analogues in replicating DNA, coupled with antibody and fluorophore staining, allows analysis of cell proliferation, but is currently limited to monolayer cultures, fixed cells and end-point assays. We describe a simple microscopy imaging method for live real-time analysis of cell proliferation, S phase progression over several division cycles, effects of anti-proliferative drugs and other applications. It is based on the prominent (~ 1.7-fold) quenching of fluorescence lifetime of a common cell-permeable nuclear stain, Hoechst 33342 upon the incorporation of 5-bromo-2'-deoxyuridine (BrdU) in genomic DNA and detection by fluorescence lifetime imaging microscopy (FLIM)...
2016: PloS One
https://www.readbyqxmd.com/read/27956139/characterization-of-stem-cell-derived-liver-and-intestinal-organoids-as-a-model-system-to-study-nuclear-receptor-biology
#10
Ingrid T G W Bijsmans, Alexandra Milona, Noortje Ijssennagger, Ellen C L Willemsen, José M Ramos Pittol, Johan W Jonker, Katja Lange, Guido J E J Hooiveld, Saskia W C van Mil
Nuclear receptors (NRs) are ligand-activated transcription factors regulating a large variety of processes involved in reproduction, development, and metabolism. NRs are ideal drug targets because they are activated by lipophilic ligands that easily pass cell membranes. Immortalized cell lines recapitulate NR biology poorly and generating primary cultures is laborious and requires a constant need for donor material. There is a clear need for development of novel preclinical model systems that better resemble human physiology...
December 10, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27951586/nlrc3-is-an-inhibitory-sensor-of-pi3k-mtor-pathways-in-cancer
#11
Rajendra Karki, Si Ming Man, R K Subbarao Malireddi, Sannula Kesavardhana, Qifan Zhu, Amanda R Burton, Bhesh Raj Sharma, Xiaopeng Qi, Stephane Pelletier, Peter Vogel, Philip Rosenstiel, Thirumala-Devi Kanneganti
NLRs (nucleotide-binding domain and leucine-rich repeats) belong to a large family of cytoplasmic sensors that regulate an extraordinarily diverse range of biological functions. One of these functions is to contribute to immunity against infectious diseases, but dysregulation of their functional activity leads to the development of inflammatory and autoimmune diseases. Cytoplasmic innate immune sensors, including NLRs, are central regulators of intestinal homeostasis. NLRC3 (also known as CLR16.2 or NOD3) is a poorly characterized member of the NLR family and was identified in a genomic screen for genes encoding proteins bearing leucine-rich repeats (LRRs) and nucleotide-binding domains...
December 12, 2016: Nature
https://www.readbyqxmd.com/read/27941880/different-in-vivo-and-in-vitro-transformation-of-intestinal-stem-cells-in-mismatch-repair-deficiency
#12
K Keysselt, T Kreutzmann, K Rother, C Kerner, K Krohn, J Przybilla, P Buske, H Löffler-Wirth, M Loeffler, J Galle, G Aust
Mutations in mismatch repair (MMR) genes result in microsatellite instability (MSI) and early onset of colorectal cancer. To get mechanistic insights into the time scale, sequence and frequency of intestinal stem cell (ISC) transformation, we quantified MSI and growth characteristics of organoids of Msh2-deficient and control mice from birth until tumor formation and related them to tissue gene expression. Although in Msh2-deficient organoids MSI continuously increased from birth, growth characteristics remained stable at first...
December 12, 2016: Oncogene
https://www.readbyqxmd.com/read/27939883/indispensable-role-of-notch-ligand-dependent-signaling-in-the-proliferation-and-stem-cell-niche-maintenance-of-apc-deficient-intestinal-tumors
#13
Toru Nakata, Hiromichi Shimizu, Sayaka Nagata, Go Ito, Satoru Fujii, Kohei Suzuki, Ami Kawamoto, Fumiaki Ishibashi, Reiko Kuno, Sho Anzai, Tatsuro Murano, Tomohiro Mizutani, Shigeru Oshima, Kiichiro Tsuchiya, Tetsuya Nakamura, Katsuto Hozumi, Mamoru Watanabe, Ryuichi Okamoto
Ligand-dependent activation of Notch signaling is required to maintain the stem-cell niche of normal intestinal epithelium. However, the precise role of Notch signaling in the maintenance of the intestinal tumor stem cell niche and the importance of the RBPJ-independent non-canonical pathway in intestinal tumors remains unknown. Here we show that Notch signaling was activated in LGR5(+ve) cells of APC-deficient mice intestinal tumors. Accordingly, Notch ligands, including Jag1, Dll1, and Dll4, were expressed in these tumors...
December 8, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27939219/induced-quiescence-of-lgr5-stem-cells-in-intestinal-organoids-enables-differentiation-of-hormone-producing-enteroendocrine-cells
#14
Onur Basak, Joep Beumer, Kay Wiebrands, Hiroshi Seno, Alexander van Oudenaarden, Hans Clevers
Lgr5+ adult intestinal stem cells are highly proliferative throughout life. Single Lgr5+ stem cells can be cultured into three-dimensional organoids containing all intestinal epithelial cell types at near-normal ratios. Conditions to generate the main cell types (enterocyte, goblet cells, Paneth cells, and M cells) are well established, but signals to induce the spectrum of hormone-producing enteroendocrine cells (EECs) have remained elusive. Here, we induce Lgr5+ stem cell quiescence in vitro by blocking epidermal growth factor receptor (EGFR) or mitogen-associated protein kinase (MAPK) signaling pathways in organoids and show that their quiescent state is readily reverted...
November 17, 2016: Cell Stem Cell
https://www.readbyqxmd.com/read/27932500/notch1-and-notch2-regulate-epithelial-cell-proliferation-in-mouse-and-human-gastric-corpus
#15
Elise S Demitrack, Gail B Gifford, Theresa M Keeley, Nobukatsu Horita, Andrea Todisco, D Kim Turgeon, Christian W Siebel, Linda C Samuelson
The Notch signaling pathway is known to regulate stem cells and epithelial cell homeostasis in gastrointestinal tissues; however, Notch function in the corpus region of the stomach is poorly understood. In this study we examined the consequences of Notch inhibition and activation on cellular proliferation and differentiation and defined the specific Notch receptors functioning in the mouse and human corpus. Notch pathway activity was observed in the mouse corpus epithelium, and gene expression analysis revealed NOTCH1 and NOTCH2 to be the predominant Notch receptors in both mouse and human...
December 8, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/27927684/in-vitro-patterning-of-pluripotent-stem-cell-derived-intestine-recapitulates-in-vivo-human-development
#16
Yu-Hwai Tsai, Roy Nattiv, Priya H Dedhia, Melinda S Nagy, Alana M Chin, Matthew Thomson, Ophir Klein, Jason Spence
The intestine plays a central role in digestion, nutrient absorption and metabolism, with individual regions of the intestine having distinct functional roles. For example, the most proximal region of the small intestine, the duodenum, is associated with absorption of micronutrients such as iron and folate, whereas the more distal ileum is responsible for recycling bile salts. Many examples of region-specific gene expression in the adult intestine are known, but how intestinal regional identity is established during development is a largely open question...
December 7, 2016: Development
https://www.readbyqxmd.com/read/27901089/a-silac-based-method-for-quantitative-proteomic-analysis-of-intestinal-organoids
#17
Alexis Gonneaud, Christine Jones, Naomie Turgeon, Dominique Lévesque, Claude Asselin, François Boudreau, François-Michel Boisvert
Organoids have the potential to bridge 3D cell culture to tissue physiology by providing a model resembling in vivo organs. Long-term growing organoids were first isolated from intestinal crypt cells and recreated the renewing intestinal epithelial niche. Since then, this technical breakthrough was applied to many other organs, including prostate, liver, kidney and pancreas. We describe here how to apply a SILAC-based quantitative proteomic approach to measure protein expression changes in intestinal organoids under different experimental conditions...
November 30, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27899814/neurogastroenterology-engineering-human-intestinal-organoids-with-a-functional-ens
#18
Katrina Ray
No abstract text is available yet for this article.
January 2017: Nature Reviews. Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/27889570/inhibitor-of-apoptosis-protein-1-regulates-tumor-necrosis-factor-mediated-destruction-of-intestinal-epithelial-cells
#19
Thomas Grabinger, Konstantin J Bode, Janine Demgenski, Carina Seitz, M Eugenia Delgado, Feodora Kostadinova, Cindy Reinhold, Nima Etemadi, Sabine Wilhelm, Matthias Schweinlin, Kay Hänggi, Janin Knop, Christof Hauck, Heike Walles, John Silke, Harald Wajant, Ueli Nachbur, W Wei-Lynn Wong, Thomas Brunner
BACKGROUND AND AIMS: Tumor necrosis factor (TNF) is a cytokine that promotes inflammation and contributes to pathogenesis of inflammatory bowel diseases. Unlike other cells and tissues, intestinal epithelial cells undergo rapid cell death upon exposure to TNF, by unclear mechanisms. We investigated the roles of inhibitor of apoptosis proteins (IAPs) in the regulation of TNF-induced cell death in the intestinal epithelium of mice and intestinal organoids. METHODS: RNA from cell lines and tissues and analyzed by quantitative PCR, protein levels were analyzed by immunoblot assays...
November 23, 2016: Gastroenterology
https://www.readbyqxmd.com/read/27888356/intestinal-stem-cell-transplantation
#20
REVIEW
Tetsuya Nakamura, Mamoru Watanabe
Organoid technologies to expand intestinal epithelial cells are gaining increasing attention as a useful tool to investigate many aspects of intestinal epithelial biology and pathology. One important application of organoid systems would be to use intestinal epithelial cells expanded in culture for following transplantation experiments. In this article, we present a brief overview of the studies that have succeeded in generating new epithelial tissues in the surface of native intestines in mice by organoid transplantation...
November 25, 2016: Journal of Gastroenterology
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