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intestinal organoids

Seyed Ramin Pajoumshariati, Morteza Azizi, Daniel Wesner, Paula G Miller, Michael Shuler, Alireza Abbaspourrad
Microfluidic-based cell encapsulation has promising potential in therapeutic applications. It also provides a unique approach for studying cellular dynamics and interactions, though this concept has not yet been fully explored. No in vitro model currently exists that allows us to study the interaction between crypt cells and Peyer's patch immune cells due to the difficulty in recreating with sufficient control the two different microenvironments in the intestine in which these cell types belong. However, we demonstrate that our microfluidic technique is able to provide such precise control and that these cells can proliferate inside the microgels...
February 23, 2018: ACS Applied Materials & Interfaces
Michael K Dame, Durga Attili, Shannon D McClintock, Priya H Dedhia, Peter Ouillette, Olaf Hardt, Alana M Chin, Xiang Xue, Julie Laliberte, Erica L Katz, Gina M Newsome, David R Hill, Alyssa J Miller, Yu-Hwai Tsai, David Agorku, Christopher H Altheim, Andreas Bosio, Becky Simon, Linda C Samuelson, Jay A Stoerker, Henry D Appelman, James Varani, Max S Wicha, Dean E Brenner, Yatrik M Shah, Jason R Spence, Justin A Colacino
The intestine is maintained by stem cells located at the base of crypts and distinguished by the expression of LGR5. Genetically engineered mouse models have provided a wealth of information about intestinal stem cells, while less is known about human intestinal stem cells due to difficulty detecting and isolating these cells. We established an organoid repository from patient-derived adenomas, adenocarcinomas, and normal colon, which we analyzed for variants in 71 colorectal cancer (CRC) associated genes. Normal and neoplastic colon tissue organoids were analyzed by immunohistochemistry and fluorescent-activated cell sorting for LGR5...
February 21, 2018: Development
Myeong-Ok Nam, Soojung Hahn, Joo Hyun Jee, Tae-Sun Hwang, Ho Yoon, Dong Hyeon Lee, Min-Soo Kwon, Jongman Yoo
Organoids, a multi-cellular and organ-like structure cultured in vitro , can be used in a variety of fields such as disease modeling, drug discovery, or cell therapy development. When organoids derived from Lgr5 stem cells are cultured ex vivo , recombinant R-spondin-1 protein should be added at a high concentration for the initiation and maintenance of the organoids. Because the addition of large amounts of R-spondin-1 greatly increases the cost of organoids, the organoids grown with R-spondin-1 are not practical for large-scale drug screening and for the development of therapeutic agents...
January 19, 2018: Oncotarget
Shusuke Toden, Preethi Ravindranathan, Jinghua Gu, Jacob Cardenas, Madelaine Yuchang, Ajay Goel
Proanthocyanidins are a heterogeneous group of flavan-3-ol or flavan-3,4-diol oligomers present in various fruits and vegetables. In particular, the smaller oligomeric subset of proanthocyanidins, termed the oligomeric proanthocyanidins (OPCs) appear to have potent anti-tumorigenic properties, but the underlying mechanisms for their effectiveness remain unclear. Herein, we utilized a series of in vitro, in vivo and patient-derived organoid approaches to systematically investigate the chemoprotective role of OPCs in colorectal cancer...
February 20, 2018: Scientific Reports
Qihang Hou, Lulu Ye, Haofei Liu, Lulu Huang, Qian Yang, J R Turner, Qinghua Yu
The regeneration of intestinal epithelial are maintained by continuous differentiation and proliferation of intestinal stem cells (ISCs) under physiological and pathological conditions. However, little is known about the regulatory effect of intestinal microbiota on its recovery ability to repair damaged mucosal barrier. In this study, we established intestinal organoids and lamina propria lymphocytes (LPLs) co-cultured system, plus mice experiments, to explore the protective effect of Lactobacillus reuteri D8 on integrity of intestinal mucosa...
February 19, 2018: Cell Death and Differentiation
Alistair J Langlands, Thomas D Carroll, Yu Chen, Inke Näthke
More than 90% of colorectal cancers carry mutations in Apc that drive tumourigenesis. A 'just-right' signalling model proposes that Apc mutations stimulate optimal, but not excessive Wnt signalling, resulting in a growth advantage of Apc mutant over wild-type cells. Reversal of this growth advantage constitutes a potential therapeutic approach. We utilised intestinal organoids to compare the growth of Apc mutant and wild-type cells. Organoids derived from Apc Min/+ mice recapitulate stages of intestinal polyposis in culture...
February 15, 2018: Cell Death & Disease
Magdalena Kasendra, Alessio Tovaglieri, Alexandra Sontheimer-Phelps, Sasan Jalili-Firoozinezhad, Amir Bein, Angeliki Chalkiadaki, William Scholl, Cheng Zhang, Hannah Rickner, Camilla A Richmond, Hu Li, David T Breault, Donald E Ingber
Here we describe a method for fabricating a primary human Small Intestine-on-a-Chip (Intestine Chip) containing epithelial cells isolated from healthy regions of intestinal biopsies. The primary epithelial cells are expanded as 3D organoids, dissociated, and cultured on a porous membrane within a microfluidic device with human intestinal microvascular endothelium cultured in a parallel microchannel under flow and cyclic deformation. In the Intestine Chip, the epithelium forms villi-like projections lined by polarized epithelial cells that undergo multi-lineage differentiation similar to that of intestinal organoids, however, these cells expose their apical surfaces to an open lumen and interface with endothelium...
February 13, 2018: Scientific Reports
Carlota Colomer, Pol Margalef, Jessica Gonzalez, Anna Vert, Anna Bigas, Lluis Espinosa
BACKGROUND: Colorectal cancer is a common cause of death in developed countries. Progression from adenoma to invasive carcinoma requires accumulation of mutations starting with the Adenomatous Polyposis Coli (Apc) gene. NF-κB signalling is a key element in cancer, mainly related to the activity of IKKβ. IKKα kinase also participates in this process by mechanisms that are primarily unknown. METHODS: We generated a compound mouse model with mutation in Apc and lacking intestinal epithelial IKKα, produced intestinal organoids and tumour spheroids with different genetic backgrounds, and performed immunohistochemistry and RNA-seq analysis...
February 13, 2018: British Journal of Cancer
Sara H Rouhanifard, Aime Lopez Aguilar, Lu Meng, Kelley W Moremen, Peng Wu
At the base of the intestinal crypt, long-lived Lgr5+ stem cells are intercalated by Paneth cells that provide essential niche signals for stem cell maintenance. This unique epithelial anatomy makes the intestinal crypt one of the most accessible models for the study of adult stem cell biology. The glycosylation patterns of this compartment are poorly characterized, and the impact of glycans on stem cell differentiation remains largely unexplored. We find that Paneth cells, but not Lgr5+ stem cells, express abundant terminal N-acetyllactosamine (LacNAc)...
February 1, 2018: Cell Chemical Biology
Koen C Oost, Lisa van Voorthuijsen, Arianna Fumagalli, Rik G H Lindeboom, Joep Sprangers, Manja Omerzu, Maria J Rodriguez-Colman, Maria C Heinz, Ingrid Verlaan-Klink, Madelon M Maurice, Boudewijn M T Burgering, Jacco van Rheenen, Michiel Vermeulen, Hugo J G Snippert
Organoid technology provides the possibility of culturing patient-derived colon tissue and colorectal cancers (CRCs) while maintaining all functional and phenotypic characteristics. Labeling stem cells, especially in normal and benign tumor organoids of human colon, is challenging and therefore limits maximal exploitation of organoid libraries for human stem cell research. Here, we developed STAR (stem cell Ascl2 reporter), a minimal enhancer/promoter element that reports transcriptional activity of ASCL2, a master regulator of LGR5+ intestinal stem cells...
February 6, 2018: Cell Reports
Pengyu Chang, Boyin Zhang, Lihong Shao, Wei Song, Weiyan Shi, Libo Wang, Tiankai Xu, Dong Li, Xiuzhu Gao, Yaqin Qu, Lihua Dong, Jin Wang
The chemokine C-X-C motif chemokine 12 (CXCL12) greatly impacts various biological processes in mammals, including cell survival, growth and migration. Mesenchymal stem cells (MSCs) are promising tools for carrying foreign genes to treat radiation-induced injuries in the intestinal epithelium. In this study, human adipose-derived MSCs were constructed to over-express the mouse cxcl12 gene to treat such injuries. In vitro, because of the high levels of mouse CXCL12 in conditioned medium produced by mouse cxcl12 gene-modified cells, phosphorylation of Akt at Ser473 and Erk1/2 at Thr202/Thr204 was increased within crypt cells of irradiated organoids compared with unmodified controls...
February 5, 2018: Cell Death & Disease
Bo Wang, Xin Rong, Elisa N D Palladino, Jiafang Wang, Alan M Fogelman, Martín G Martín, Waddah A Alrefai, David A Ford, Peter Tontonoz
Adequate availability of cellular building blocks, including lipids, is a prerequisite for cellular proliferation, but excess dietary lipids are linked to increased cancer risk. Despite these connections, specific regulatory relationships between membrane composition, intestinal stem cell (ISC) proliferation, and tumorigenesis are unclear. We reveal an unexpected link between membrane phospholipid remodeling and cholesterol biosynthesis and demonstrate that cholesterol itself acts as a mitogen for ISCs. Inhibition of the phospholipid-remodeling enzyme Lpcat3 increases membrane saturation and stimulates cholesterol biosynthesis, thereby driving ISC proliferation...
February 1, 2018: Cell Stem Cell
Payel Bhanja, Andrew Norris, Pooja Gupta-Saraf, Andrew Hoover, Subhrajit Saha
BACKGROUND: Radiation-induced gastrointestinal syndrome (RIGS) results from the acute loss of intestinal stem cells (ISC), impaired epithelial regeneration, and subsequent loss of the mucosal barrier, resulting in electrolyte imbalance, diarrhea, weight loss, sepsis, and mortality. The high radiosensitivity of the intestinal epithelium limits effective radiotherapy against abdominal malignancies and limits the survival of victims of nuclear accidents or terrorism. Currently, there is no approved therapy to mitigate radiation toxicity in the intestine...
February 2, 2018: Stem Cell Research & Therapy
Sarah C Pearce, Arwa Al-Jawadi, Kunihiro Kishida, Shiyan Yu, Madeleine Hu, Luke F Fritzky, Karen L Edelblum, Nan Gao, Ronaldo P Ferraris
BACKGROUND: Mammalian small intestinal tight junctions (TJ) link epithelial cells to one another and function as a permselective barrier, strictly modulating the passage of ions and macromolecules through the pore and leak pathways, respectively, thereby preventing the absorption of harmful compounds and microbes while allowing regulated transport of nutrients and electrolytes. Small intestinal epithelial permeability is ascribed primarily to the properties of TJs between adjoining enterocytes (ENTs), because there is almost no information on TJ composition and the paracellular permeability of nonenterocyte cell types that constitute a small but significant fraction of the intestinal epithelia...
February 1, 2018: BMC Biology
Tenson Cai, Yijun Qi, Albert Jergens, Michael Wannemuehler, Terrence A Barrett, Qun Wang
The intestinal epithelium of the gastrointestinal (GI) tract constantly renews itself to absorb nutrients and provide protection for the body from the outside world. Since the intestinal epithelium is constantly exposed to various chemicals and dietary components, it is critical to determine which constituents promote or inhibit intestinal epithelium health and growth rate. Intestinal organoids, three-dimensional miniature models of the intestines, represent an ex vivo tool to investigate intestinal physiology and growth patterns...
2018: PloS One
Yanchun Liu, Barrett P Cromeens, Yijie Wang, Kelli Fisher, Jed Johnson, Jason Chakroff, Gail E Besner
OBJECTIVE: The objective of this study was to compare the impact of different in vivo incubation sites on the production of tissue engineered small intestine (TESI). METHODS: Green fluorescent protein (GFP) transgenic rat pups (3-5 days) were used as donors of intestinal organoids. 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...
January 31, 2018: Tissue Engineering. Part A
Adrian Frick, Vineeta Khare, Gregor Paul, Michaela Lang, Franziska Ferk, Siegfried Knasmueller, Andrea Beer, Georg Oberhuber, Christoph Gasche
Patients with inflammatory bowel disease (IBD) have a higher risk of developing colitis-associated-cancer (CAC), however, the underlying processes of disease progression are not completely understood. Here, the molecular processes of inflammation-driven colon carcinogenesis were investigated using IL-10 deficient mice (IL-10- KO). IL-10- KO mice were euthanized after development of colitis and dysplasia. Immunohistochemistry (IHC) was performed for markers of colitis-induced DNA damage (CIDD): oxidative-DNA-lesions (8-oxoG), double-strand breaks (DSB; γH2AX) and DSB-repair...
January 29, 2018: Molecular Cancer Research: MCR
Kohei Suzuki, Tatsuro Murano, Hiromichi Shimizu, Go Ito, Toru Nakata, Satoru Fujii, Fumiaki Ishibashi, Ami Kawamoto, Sho Anzai, Reiko Kuno, Konomi Kuwabara, Junichi Takahashi, Minami Hama, Sayaka Nagata, Yui Hiraguri, Kento Takenaka, Shiro Yui, Kiichiro Tsuchiya, Tetsuya Nakamura, Kazuo Ohtsuka, Mamoru Watanabe, Ryuichi Okamoto
BACKGROUND: Intestinal stem cells (ISCs) play indispensable roles in the maintenance of homeostasis, and also in the regeneration of the damaged intestinal epithelia. However, whether the inflammatory environment of Crohn's disease (CD) affects properties of resident small intestinal stem cells remain uncertain. METHODS: CD patient-derived small intestinal organoids were established from enteroscopic biopsy specimens taken from active lesions (aCD-SIO), or from mucosa under remission (rCD-SIO)...
January 27, 2018: Journal of Gastroenterology
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
Johanna Pott, Agnieszka Martyna Kabat, Kevin Joseph Maloy
Genome-wide association studies have linked polymorphisms in the autophagy gene ATG16L1 with susceptibility to inflammatory bowel disease (IBD). However, the cell-type-specific effects of autophagy on the regulation of chronic intestinal inflammation have not been investigated. Here, we assessed the effect of myeloid-specific or intestinal epithelial cell (IEC)-specific deletion of Atg16l1 on chronic colitis triggered by the intestinal opportunistic pathogen Helicobacter hepaticus in mice. Although Atg16l1 deficiency in myeloid cells had little effect on disease, mice selectively lacking Atg16l1 in IECs (Atg16l1VC) developed severely exacerbated pathology, accompanied by elevated pro-inflammatory cytokine secretion and increased IEC apoptosis...
January 17, 2018: Cell Host & Microbe
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