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https://www.readbyqxmd.com/read/28720124/defining-the-role-of-lgr5-stem-cells-in-colorectal-cancer-from-basic-research-to-clinical-applications
#1
Masayuki Fujii, Toshiro Sato
Intestinal epithelium is structured by two distinct components: the villi and the crypts. The crypts harbor stem cells expressing Lgr5 and thus have been a representative model to study tissue stem cell functions. Recent advances in organoid technology and analytical modalities have enabled precise characterization of Lgr5(+) intestinal stem cells, providing insights into their roles in homeostasis and cancer.
July 18, 2017: Genome Medicine
https://www.readbyqxmd.com/read/28717211/epithelial-cell-specific-raptor-is-required-for-initiation-of-type-2-mucosal-immunity-in-small-intestine
#2
Bola Aladegbami, Lauren Barron, James Bao, Jason Colasanti, Christopher R Erwin, Brad W Warner, Jun Guo
Intestinal tuft cells are one of 4 secretory cell linages in the small intestine and the source of IL-25, a critical initiator of the type 2 immune response to parasite infection. When Raptor, a critical scaffold protein for mammalian target of rapamycin complex 1 (mTORC1), was acutely deleted in intestinal epithelium via Tamoxifen injection in Tritrichomonas muris (Tm) infected mice, tuft cells, IL-25 in epithelium and IL-13 in the mesenchyme were significantly reduced, but Tm burden was not affected. When Tm infected mice were treated with rapamycin, DCLK1 and IL-25 expression in enterocytes and IL-13 expression in mesenchyme were diminished...
July 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28716720/met-signaling-mediates-intestinal-crypt-villus-development-regeneration-and-adenoma-formation-and-is-promoted-by-stem-cell-cd44-isoforms
#3
Sander P J Joosten, Jurrit Zeilstra, Harmen van Andel, R Clinton Mijnals, Joost Zaunbrecher, Annet A M Duivenvoorden, Marc van de Wetering, Hans Clevers, Marcel Spaargaren, Steven T Pals
BACKGROUND & AIMS: Resistance of metastatic human colorectal cancer cells to drugs that block epidermal growth factor receptor (EGFR) signaling could be caused by aberrant activity of other receptor tyrosine kinases, activating overlapping signaling pathways. One of these receptor tyrosine kinases could be MET, the receptor for hepatocyte growth factor (HGF). We investigated how MET signaling, and its interaction with CD44 (a putative MET co-receptor regulated by Wnt signaling and highly expressed by intestinal stem cells [ISCs] and adenomas) affects intestinal homeostasis, regeneration, and adenoma formation in mini-gut organoids and mice...
July 14, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28659914/cell-polarization-and-epigenetic-status-shape-the-heterogeneous-response-to-type-iii-interferons-in-intestinal-epithelial-cells
#4
Sudeep Bhushal, Markus Wolfsmüller, Tharini A Selvakumar, Lucas Kemper, Dagmar Wirth, Mathias W Hornef, Hansjörg Hauser, Mario Köster
Type I and type III interferons (IFNs) are crucial components of the first-line antiviral host response. While specific receptors for both IFN types exist, intracellular signaling shares the same Jak-STAT pathway. Due to its receptor expression, IFN-λ responsiveness is restricted mainly to epithelial cells. Here, we display IFN-stimulated gene induction at the single cell level to comparatively analyze the activities of both IFN types in intestinal epithelial cells and mini-gut organoids. Initially, we noticed that the response to both types of IFNs at low concentrations is based on a single cell decision-making determining the total cell intrinsic antiviral activity...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28648659/enterochromaffin-cells-are-gut-chemosensors-that-couple-to-sensory-neural-pathways
#5
Nicholas W Bellono, James R Bayrer, Duncan B Leitch, Joel Castro, Chuchu Zhang, Tracey A O'Donnell, Stuart M Brierley, Holly A Ingraham, David Julius
Dietary, microbial, and inflammatory factors modulate the gut-brain axis and influence physiological processes ranging from metabolism to cognition. The gut epithelium is a principal site for detecting such agents, but precisely how it communicates with neural elements is poorly understood. Serotonergic enterochromaffin (EC) cells are proposed to fulfill this role by acting as chemosensors, but understanding how these rare and unique cell types transduce chemosensory information to the nervous system has been hampered by their paucity and inaccessibility to single-cell measurements...
June 29, 2017: Cell
https://www.readbyqxmd.com/read/28648364/differentiation-of-human-pluripotent-stem-cells-into-colonic-organoids-via-transient-activation-of-bmp-signaling
#6
Jorge O Múnera, Nambirajan Sundaram, Scott A Rankin, David Hill, Carey Watson, Maxime Mahe, Jefferson E Vallance, Noah F Shroyer, Katie L Sinagoga, Adrian Zarzoso-Lacoste, Jonathan R Hudson, Jonathan C Howell, Praneet Chatuvedi, Jason R Spence, John M Shannon, Aaron M Zorn, Michael A Helmrath, James M Wells
Gastric and small intestinal organoids differentiated from human pluripotent stem cells (hPSCs) have revolutionized the study of gastrointestinal development and disease. Distal gut tissues such as cecum and colon, however, have proved considerably more challenging to derive in vitro. Here we report the differentiation of human colonic organoids (HCOs) from hPSCs. We found that BMP signaling is required to establish a posterior SATB2+ domain in developing and postnatal intestinal epithelium. Brief activation of BMP signaling is sufficient to activate a posterior HOX code and direct hPSC-derived gut tube cultures into HCOs...
July 6, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28646678/bioengineering-for-intestinal-organoid-cultures
#7
REVIEW
Ge-Ah Kim, Jason R Spence, Shuichi Takayama
Recent advances allow access to human cell-based intestinal organoids that recreate human physiology to levels not possible with conventional 2D cell cultures. Despite their huge potential, there are many challenges that remain. This review will cover recent bioengineering approaches to improve organoid maturation, scale up, reproducibility and analysis. The first section covers the advances in engineering the culture environment, followed by the section on tools for micro-manipulation and analysis of organoids...
June 21, 2017: Current Opinion in Biotechnology
https://www.readbyqxmd.com/read/28643936/phenotypic-analysis-of-organoids-by-proteomics
#8
REVIEW
Alexis Gonneaud, Claude Asselin, François Boudreau, François-Michel Boisvert
The development of 3D cell cultures into self-organizing organ-like structures named organoids provides a model that better reflects in vivo organ physiology and their functional properties. Organoids have been established from several organs, such as the intestine, prostate, brain, liver, kidney and pancreas. With recent advances in high-throughput and -omics profiling technologies, it is now possible to study the mechanisms of cellular organisation at the systems level. It is therefore not surprising that these methods are now used to characterize organoids at the transcriptomic, proteomic, chromatin state and transcription factor DNA-binding levels...
June 23, 2017: Proteomics
https://www.readbyqxmd.com/read/28634937/establishment-of-3d-intestinal-organoid-cultures-from-intestinal-stem-cells
#9
Shinya Sugimoto, Toshiro Sato
The intestinal epithelium is the most rapidly renewed tissue in adult mammals, and its renewal is strictly controlled by intestinal stem cells. Extensive studies using genetic models of intestinal epithelium have revealed the mechanisms underlying the self-renewal of intestinal stem cells. Exploiting this knowledge, we developed a novel 3D culture system that enables the outgrowth of intestinal Lgr5(+) stem cells derived from mouse and human tissues into ever-expanding crypt-villus mini-guts, known as intestinal epithelial organoids...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28628120/intestinal-cancer-progression-by-mutant-p53-through-the-acquisition-of-invasiveness-associated-with-complex-glandular-formation
#10
M Nakayama, E Sakai, K Echizen, Y Yamada, H Oshima, T-S Han, R Ohki, S Fujii, A Ochiai, S Robine, D C Voon, T Tanaka, M M Taketo, M Oshima
Tumor suppressor TP53 is frequently mutated in colorectal cancer (CRC), and most mutations are missense type. Although gain-of-functions by mutant p53 have been demonstrated experimentally, the precise mechanism for malignant progression in in vivo tumors remains unsolved. We generated Apc(Δ716) Trp53(LSL•R270H) villin-CreER compound mice, in which mutant p53(R270H) was expressed in the intestinal epithelia upon tamoxifen treatment, and examined the intestinal tumor phenotypes and tumor-derived organoids...
June 19, 2017: Oncogene
https://www.readbyqxmd.com/read/28628110/colonic-organoids-derived-from-human-induced-pluripotent-stem-cells-for-modeling-colorectal-cancer-and-drug-testing
#11
Miguel Crespo, Eduardo Vilar, Su-Yi Tsai, Kyle Chang, Sadaf Amin, Tara Srinivasan, Tuo Zhang, Nina H Pipalia, Huanhuan Joyce Chen, Mavee Witherspoon, Miriam Gordillo, Jenny Zhaoying Xiang, Frederick R Maxfield, Steven Lipkin, Todd Evans, Shuibing Chen
With the goal of modeling human disease of the large intestine, we sought to develop an effective protocol for deriving colonic organoids (COs) from differentiated human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs). Extensive gene and immunohistochemical profiling confirmed that the derived COs represent colon rather than small intestine, containing stem cells, transit-amplifying cells, and the expected spectrum of differentiated cells, including goblet and endocrine cells. We applied this strategy to iPSCs derived from patients with familial adenomatous polyposis (FAP-iPSCs) harboring germline mutations in the WNT-signaling-pathway-regulator gene encoding APC, and we generated COs that exhibit enhanced WNT activity and increased epithelial cell proliferation, which we used as a platform for drug testing...
July 2017: Nature Medicine
https://www.readbyqxmd.com/read/28614706/enhanced-rate-of-acquisition-of-point-mutations-in-mouse-intestinal-adenomas-compared-to-normal-tissue
#12
Natalia Lugli, Vasilis S Dionellis, Paloma Ordóñez-Morán, Irene Kamileri, Sotirios K Sotiriou, Joerg Huelsken, Thanos D Halazonetis
The most prevalent single-nucleotide substitution (SNS) found in cancers is a C-to-T substitution in the CpG motif. It has been proposed that many of these SNSs arise during organismal aging, prior to transformation of a normal cell into a precancerous/cancer cell. Here, we isolated single intestinal crypts derived from normal tissue or from adenomas of Apc(min/+) mice, expanded them minimally in vitro as organoids, and performed exome sequencing to identify point mutations that had been acquired in vivo at the single-cell level...
June 13, 2017: Cell Reports
https://www.readbyqxmd.com/read/28614372/intestinal-organoids-model-human-responses-to-infection-by-commensal-and-shiga-toxin-producing-escherichia-coli
#13
Sayali S Karve, Suman Pradhan, Doyle V Ward, Alison A Weiss
Infection with Shiga toxin (Stx) producing Escherichia coli O157:H7 can cause the potentially fatal complication hemolytic uremic syndrome, and currently only supportive therapy is available. Lack of suitable animal models has hindered study of this disease. Induced human intestinal organoids (iHIOs), generated by in vitro differentiation of pluripotent stem cells, represent differentiated human intestinal tissue. We show that iHIOs with addition of human neutrophils can model E. coli intestinal infection and innate cellular responses...
2017: PloS One
https://www.readbyqxmd.com/read/28607910/exploiting-induced-senescence-in-intestinal-organoids-to-drive-enteroendocrine-cell-expansion
#14
EDITORIAL
Robert G Ramsay, Helen E Abud
No abstract text is available yet for this article.
2017: Stem Cell Investigation
https://www.readbyqxmd.com/read/28600348/loss-of-the-wnt-receptor-frizzled7-in-the-gastric-epithelium-is-deleterious-and-triggers-rapid-repopulation-in-vivo
#15
Dustin J Flanagan, Nicholas Barker, Cameron Nowell, Hans Clevers, Matthias Ernst, Toby J Phesse, Elizabeth Vincan
The gastric epithelium consists of tubular glandular units each containing several differentiated cells types, and populations of stem cells, which enable the stomach to secrete the acid, mucus and various digestive enzymes required for its function. Cell signalling provides cues to regulate development and homeostasis of adult tissues, however very little is known about which cell signalling pathways are required for homeostasis of the gastric epithelium. Many diseases, such as cancer, arise as a result of deregulation to signalling pathways that regulate homeostasis of the diseased organ...
June 9, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28599598/uniform-neural-tissue-models-produced-on-synthetic-hydrogels-using-standard-culture-techniques
#16
Christopher Barry, Matthew T Schmitz, Nicholas E Propson, Zhonggang Hou, Jue Zhang, Bao K Nguyen, Jennifer M Bolin, Peng Jiang, Brian E McIntosh, Mitchell D Probasco, Scott Swanson, Ron Stewart, James A Thomson, Michael P Schwartz, William L Murphy
The aim of the present study was to test sample reproducibility for model neural tissues formed on synthetic hydrogels. Human embryonic stem (ES) cell-derived precursor cells were cultured on synthetic poly(ethylene glycol) (PEG) hydrogels to promote differentiation and self-organization into model neural tissue constructs. Neural progenitor, vascular, and microglial precursor cells were combined on PEG hydrogels to mimic developmental timing, which produced multicomponent neural constructs with 3D neuronal and glial organization, organized vascular networks, and microglia with ramified morphologies...
January 1, 2017: Experimental Biology and Medicine
https://www.readbyqxmd.com/read/28593182/the-circadian-clock-gene-bmal1-coordinates-intestinal%C3%A2-regeneration
#17
Kyle Stokes, Abrial Cooke, Hanna Chang, David R Weaver, David T Breault, Phillip Karpowicz
BACKGROUND & AIMS: The gastrointestinal syndrome is an illness of the intestine caused by high levels of radiation. It is characterized by extensive loss of epithelial tissue integrity, which initiates a regenerative response by intestinal stem and precursor cells. The intestine has 24-hour rhythms in many physiological functions that are believed to be outputs of the circadian clock: a molecular system that produces 24-hour rhythms in transcription/translation. Certain gastrointestinal illnesses are worsened when the circadian rhythms are disrupted, but the role of the circadian clock in gastrointestinal regeneration has not been studied...
July 2017: Cellular and Molecular Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/28559141/establishment-of-a-refined-culture-method-for-rat-colon-organoids
#18
Hiroyuki Isshiki, Yoshiaki Arimura, Kanna Nagaishi, Kentaro Kawakami, Kei Onodera, Kentaro Yamashita, Yasuyoshi Naishiro, Mineko Fujimiya, Kohzoh Imai, Yasuhisa Shinomura
BACKGROUND: Methods for the artificial three-dimensional (3D) culture of mouse and human small-intestinal and large-intestinal stem cells have been established with CD24(+) or Paneth cell niches. In contrast, no studies have established stable 3D culture for rat colon stem cells. In this study, we established an advanced method for efficient rat colonic stem cell culture. METHODS: Using various tissue homogenates, we investigated the colonic organoid forming capacity under the TMDU protocol immediately adjacent to Ootani's 3D culture assembly in the same culture dish...
May 27, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28550311/organoid-based-epithelial-to-mesenchymal-transition-oemt-model-from-an-intestinal-fibrosis-perspective
#19
Soojung Hahn, Myeong-Ok Nam, Jung Hyun Noh, Dong Hyeon Lee, Hyun Wook Han, Duk Hwan Kim, Ki Baik Hahm, Sung Pyo Hong, Jun-Hwan Yoo, Jongman Yoo
The current in vitro or in vivo intestinal fibrosis models have many limitations. Recent advancements in the isolation and culturing of organoids has led to development of various three-dimensional (3D) intestinal disease models with in vivo physiology. In this study, we generated an organoid-based epithelial to mesenchymal transition (OEMT) model, which could be used as a novel intestinal fibrosis model. Intestinal epithelial organoids (IEOs) were isolated and cultured from the small intestines of normal mice...
May 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28550196/il-6-signaling-regulates-small-intestinal-crypt-homeostasis
#20
Victoria Jeffery, Andrew J Goldson, Jack R Dainty, Marcello Chieppa, Anastasia Sobolewski
Gut homeostasis is a tightly regulated process requiring finely tuned complex interactions between different cell types, growth factors, or cytokines and their receptors. Previous work has implicated a role for IL-6 and mucosal immune cells in intestinal regeneration following injury and in promoting inflammation and cancer. We hypothesized that IL-6 signaling could also modulate crypt homeostasis. Using mouse in vitro crypt organoid and in vivo models, this study first demonstrated that exogenous IL-6 promoted crypt organoid proliferation and increased stem cell numbers through pSTAT3 activation in Paneth cells...
May 26, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
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