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Wei Gong, Mengzheng Guo, Zhibo Han, Yan Wang, Ping Yang, Chang Xu, Qin Wang, Liqing Du, Qian Li, Hui Zhao, Feiyue Fan, Qiang Liu
The loss of stem cells residing in the base of the intestinal crypt has a key role in radiation-induced intestinal injury. In particular, Lgr5(+) intestinal stem cells (ISCs) are indispensable for intestinal regeneration following exposure to radiation. Mesenchymal stem cells (MSCs) have previously been shown to improve intestinal epithelial repair in a mouse model of radiation injury, and, therefore, it was hypothesized that this protective effect is related to Lgr5(+) ISCs. In this study, it was found that, following exposure to radiation, transplantation of MSCs improved the survival of the mice, ameliorated intestinal injury and increased the number of regenerating crypts...
2016: Cell Death & Disease
Julie G In, Jennifer Foulke-Abel, Mary K Estes, Nicholas C Zachos, Olga Kovbasnjuk, Mark Donowitz
The development of indefinitely propagating human 'mini-guts' has led to a rapid advance in gastrointestinal research related to transport physiology, developmental biology, pharmacology, and pathophysiology. These mini-guts, also called enteroids or colonoids, are derived from LGR5(+) intestinal stem cells isolated from the small intestine or colon. Addition of WNT3A and other growth factors promotes stemness and results in viable, physiologically functional human intestinal or colonic cultures that develop a crypt-villus axis and can be differentiated into all intestinal epithelial cell types...
September 28, 2016: Nature Reviews. Gastroenterology & Hepatology
Thomas E Wallach, James R Bayrer
The development of sustainable intestinal organoid cell culture has emerged as a new modality for the study of intestinal function and cellular processes. Organoid culture is providing a new test-bed for therapeutic research and development. Intestinal organoids, self-renewing three-dimensional structures comprised of intestinal stem cells and their differentiated epithelial progeny allow for more facile and robust exploration of cellular activity, cell organization and structure, genetic manipulation, and vastly more physiologic modeling of intestinal response to stimuli as compared to traditional two dimensional cell line cultures...
September 14, 2016: Journal of Pediatric Gastroenterology and Nutrition
Khalil Ettayebi, Sue E Crawford, Kosuke Murakami, James R Broughman, Umesh Karandikar, Victoria R Tenge, Frederick H Neill, Sarah E Blutt, Xi-Lei Zeng, Lin Qu, Baijun Kou, Antone R Opekun, Douglas Burrin, David Y Graham, Sasirekha Ramani, Robert L Atmar, Mary K Estes
The major barrier to research and development of effective interventions for human noroviruses (HuNoVs) has been the lack of a robust and reproducible in vitro cultivation system. HuNoVs are the leading cause of gastroenteritis worldwide. We report the successful cultivation of multiple HuNoV strains in enterocytes in stem cell-derived, nontransformed human intestinal enteroid monolayer cultures. Bile, a critical factor of the intestinal milieu, is required for strain-dependent HuNoV replication. Lack of appropriate histoblood group antigen expression in intestinal cells restricts virus replication, and infectivity is abrogated by inactivation (e...
September 23, 2016: Science
Jessica Tsalikis, Qun Pan, Ivan Tattoli, Charles Maisonneuve, Benjamin J Blencowe, Dana J Philpott, Stephen E Girardin
BACKGROUND: The intestinal epithelium plays a critical role in nutrient absorption and innate immune defense. Recent studies showed that metabolic stress pathways, in particular the integrated stress response (ISR), control intestinal epithelial cell fate and function. Here, we used RNA-seq to analyze the global transcript level and alternative splicing responses of primary murine enteroids undergoing two distinct ISR-triggering stresses, endoplasmic reticulum (ER) stress and nutrient starvation...
2016: BMC Genomics
Xiang Xue, Sadeesh K Ramakrishnan, Kevin Weisz, Daniel Triner, Liwei Xie, Durga Attili, Asha Pant, Balázs Győrffy, Mingkun Zhan, Christin Carter-Su, Karin M Hardiman, Thomas D Wang, Michael K Dame, James Varani, Dean Brenner, Eric R Fearon, Yatrik M Shah
Dietary iron intake and systemic iron balance are implicated in colorectal cancer (CRC) development, but the means by which iron contributes to CRC are unclear. Gene expression and functional studies demonstrated that the cellular iron importer, divalent metal transporter 1 (DMT1), is highly expressed in CRC through hypoxia-inducible factor 2α-dependent transcription. Colon-specific Dmt1 disruption resulted in a tumor-selective inhibitory effect of proliferation in mouse colon tumor models. Proteomic and genomic analyses identified an iron-regulated signaling axis mediated by cyclin-dependent kinase 1 (CDK1), JAK1, and STAT3 in CRC progression...
September 13, 2016: Cell Metabolism
Barrett P Cromeens, Yanchun Liu, Johnathan Stathopoulos, Yijie Wang, Jed Johnson, Gail E Besner
BACKGROUND: Short bowel syndrome is a life-threatening condition with few solutions. Tissue-engineered intestine (TEI) is a potential treatment, but donor intestine is a limiting factor. Expanded epithelial surrogates termed enteroids may serve as a potential donor source. MATERIALS AND METHODS: To produce TEI from enteroids, crypts were harvested from mice and enteroid cultures established. Enteroids were seeded onto polymer scaffolds using Matrigel or culture medium and implanted in immunosuppressed mice for 4 wk...
July 2016: Journal of Surgical Research
Megan B Wood, Daniel Rios, Ifor R Williams
Microfold (M) cells are phagocytic intestinal epithelial cells in the follicle-associated epithelium of Peyer's patches that transport particulate antigens from the gut lumen into the subepithelial dome. Differentiation of M cells from epithelial stem cells in intestinal crypts requires the cytokine receptor activator of NF-κB ligand (RANKL) and the transcription factor Spi-B. We used three-dimensional enteroid cultures established with small intestinal crypts from mice as a model system to investigate signaling pathways involved in M cell differentiation and the influence of other cytokines on RANKL-induced M cell differentiation...
September 1, 2016: American Journal of Physiology. Cell Physiology
Y Wang, L Liu, D J Moore, X Shen, R M Peek, S A Acra, H Li, X Ren, D B Polk, F Yan
p40, a Lactobacillus rhamnosus GG (LGG)-derived protein, transactivates epidermal growth factor receptor (EGFR) in intestinal epithelial cells, leading to amelioration of intestinal injury and inflammation. To elucidate mechanisms by which p40 regulates mucosal immunity to prevent inflammation, this study aimed to determine the effects and mechanisms of p40 on regulation of a proliferation-inducing ligand (APRIL) expression in intestinal epithelial cells for promoting immunoglobulin A (IgA) production. p40 upregulated April gene expression and protein production in mouse small intestine epithelial (MSIE) cells, which were inhibited by blocking EGFR expression and kinase activity...
June 29, 2016: Mucosal Immunology
F Matthew Kuhlmann, Srikanth Santhanam, Pardeep Kumar, Qingwei Luo, Matthew A Ciorba, James M Fleckenstein
Because O blood group has been associated with more severe cholera infections, it has been hypothesized that cholera toxin (CT) may bind non-O blood group antigens of the intestinal mucosae, thereby preventing efficient interaction with target GM1 gangliosides required for uptake of the toxin and activation of cyclic adenosine monophosphate (cAMP) signaling in target epithelia. Herein, we show that after exposure to CT, human enteroids expressing O blood group exhibited marked increase in cAMP relative to cells derived from blood group A individuals...
August 3, 2016: American Journal of Tropical Medicine and Hygiene
Ronald Schilderink, Caroline Verseijden, Jurgen Seppen, Vanesa Muncan, Gijs R van den Brink, Tim T Lambers, Eric A van Tol, Wouter J de Jonge
In the intestinal mucosa, retinoic acid (RA) is a critical signaling molecule. RA is derived from dietary vitamin A (retinol) through conversion by aldehyde dehydrogenases (aldh). Reduced levels of short-chain fatty acids (SCFAs) are associated with pathological microbial dysbiosis, inflammatory disease, and allergy. We hypothesized that SCFAs contribute to mucosal homeostasis by enhancing RA production in intestinal epithelia. With the use of human and mouse epithelial cell lines and primary enteroids, we studied the effect of SCFAs on the production of RA...
June 1, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
Jennifer C Miguel, Adrienne A Maxwell, Jonathan J Hsieh, Lukas C Harnisch, Denise Al Alam, D Brent Polk, Ching-Ling Lien, Alastair J M Watson, Mark R Frey
Cell shedding from the intestinal villus is a key element of tissue turnover, essential to maintain health and homeostasis. However, the signals regulating this process are not well understood. We asked whether shedding is controlled by epidermal growth factor receptor (EGFR), an important driver of intestinal growth and differentiation. In 3D ileal enteroid culture and cell culture models (MDCK, IEC-6, IPEC-J2 cells), extrusion events were suppressed by EGF, as determined by direct counting of released cells or rhodamine-phalloidin labeling of condensed actin rings...
March 29, 2016: Journal of Cell Science
Andrew Scott, Joshua D Rouch, Ziyad Jabaji, Hassan A Khalil, Sergio Solorzano, Michael Lewis, Martín G Martín, Matthias G Stelzner, James C Y Dunn
PURPOSE: Current culture schema for human intestinal stem cells (hISCs) frequently rely on a 3D culture system using Matrigel™, a laminin-rich matrix derived from murine sarcoma that is not suitable for clinical use. We have developed a novel 2D culture system for the in vitro expansion of hISCs as an intestinal epithelial monolayer without the use of Matrigel. METHODS: Cadaveric duodenal samples were processed to isolate intestinal crypts from the mucosa. Crypts were cultured on a thin coat of type I collagen or laminin...
June 2016: Journal of Pediatric Surgery
Hassan A Khalil, Nan Ye Lei, Garrett Brinkley, Andrew Scott, Jiafang Wang, Upendra K Kar, Ziyad B Jabaji, Michael Lewis, Martín G Martín, James C Y Dunn, Matthias G Stelzner
Porcine models are useful for investigating therapeutic approaches to short bowel syndrome and potentially to intestinal stem cell (ISC) transplantation. Whereas techniques for the culture and genetic manipulation of ISCs from mice and humans are well established, similar methods for porcine stem cells have not been reported. Jejunal crypts were isolated from murine, human, and juvenile and adult porcine small intestine, suspended in Matrigel, and co-cultured with syngeneic intestinal subepithelial myofibroblasts (ISEMFs) or cultured without feeder cells in various culture media...
July 2016: Cell and Tissue Research
H Chung, A Vilaysane, A Lau, M Stahl, V Morampudi, A Bondzi-Simpson, J M Platnich, N A Bracey, M-C French, P L Beck, J Chun, B A Vallance, D A Muruve
Nod-like receptor, pyrin containing 3 (NLRP3) is characterized primarily as a canonical caspase-1 activating inflammasome in macrophages. NLRP3 is also expressed in the epithelium of the kidney and gut; however, its function remains largely undefined. Primary mouse tubular epithelial cells (TEC) lacking Nlrp3 displayed reduced apoptosis downstream of the tumor necrosis factor (TNF) receptor and CD95. TECs were identified as type II apoptotic cells that activated caspase-8, tBid and mitochondrial apoptosis via caspase-9, responses that were reduced in Nlrp3-/- cells...
August 2016: Cell Death and Differentiation
Vishruth K Reddy, Sarah P Short, Caitlyn W Barrett, Mukul K Mittal, Cody E Keating, Joshua J Thompson, Elizabeth I Harris, Frank Revetta, David M Bader, Thomas Brand, M Kay Washington, Christopher S Williams
Blood vessel epicardial substance (BVES/Popdc1) is a junctional-associated transmembrane protein that is underexpressed in a number of malignancies and regulates epithelial-to-mesenchymal transition. We previously identified a role for BVES in regulation of the Wnt pathway, a modulator of intestinal stem cell programs, but its role in small intestinal (SI) biology remains unexplored. We hypothesized that BVES influences intestinal stem cell programs and is critical to SI homeostasis after radiation injury. At baseline, Bves(-/-) mice demonstrated increased crypt height, as well as elevated proliferation and expression of the stem cell marker Lgr5 compared to wild-type (WT) mice...
June 2016: Stem Cells
Kathryn Hamilton, Priya Chatterji, Sarah Andres, Emma Lundsmith, Kelly Whelan, Rei Mizuno, Veronique Giroux, Amanda Mah, Lillian Chua, Philip Hicks, Laurianne Van Landeghem, P Lund, Gary Wu, Anil Rustgi
BACKGROUND: IMP1 (Insulin-like growth factor-2 mRNA binding protein 1) is essential for normal gut development and aberrant overexpression promotes colorectal tumors; however, the role of IMP1 in epithelial homeostasis in the adult intestine remains unclear. Our preliminary findings suggest that Imp1 loss may alter autophagy in intestinal epithelium during homeostasis and response to injury. Recent studies have linked aberrations in autophagy to Crohn's disease. We therefore sought to determine if Imp1-mediated changes in autophagy may affect response to injury in the intestine epithelium and whether Imp1 expression is altered in Crohn's disease patients...
March 2016: Inflammatory Bowel Diseases
Joshua D Rouch, Andrew Scott, Nan Ye Lei, R Sergio Solorzano-Vargas, Jiafang Wang, Elaine M Hanson, Masae Kobayashi, Michael Lewis, Matthias G Stelzner, James C Y Dunn, Lars Eckmann, Martín G Martín
BACKGROUND & AIMS: Intestinal microfold (M) cells are specialized epithelial cells that act as gatekeepers of luminal antigens in the intestinal tract. They play a critical role in the intestinal mucosal immune response through transport of viruses, bacteria and other particles and antigens across the epithelium to immune cells within Peyer's patch regions and other mucosal sites. Recent studies in mice have demonstrated that M cells are generated from Lgr5+ intestinal stem cells (ISCs), and that infection with Salmonella enterica serovar Typhimurium increases M cell formation...
2016: PloS One
Jennifer Foulke-Abel, Julie In, Jianyi Yin, Nicholas C Zachos, Olga Kovbasnjuk, Mary K Estes, Hugo de Jonge, Mark Donowitz
BACKGROUND & AIMS: Human intestinal crypt-derived enteroids are a model of intestinal ion transport that require validation by comparison with cell culture and animal models. We used human small intestinal enteroids to study neutral Na(+) absorption and stimulated fluid and anion secretion under basal and regulated conditions in undifferentiated and differentiated cultures to show their functional relevance to ion transport physiology and pathophysiology. METHODS: Human intestinal tissue specimens were obtained from an endoscopic biopsy or surgical resections performed at Johns Hopkins Hospital...
March 2016: Gastroenterology
Nicholas C Zachos, Olga Kovbasnjuk, Jennifer Foulke-Abel, Julie In, Sarah E Blutt, Hugo R de Jonge, Mary K Estes, Mark Donowitz
Identification of Lgr5 as the intestinal stem cell marker as well as the growth factors necessary to replicate adult intestinal stem cell division has led to the establishment of the methods to generate "indefinite" ex vivo primary intestinal epithelial cultures, termed "mini-intestines." Primary cultures developed from isolated intestinal crypts or stem cells (termed enteroids/colonoids) and from inducible pluripotent stem cells (termed intestinal organoids) are being applied to study human intestinal physiology and pathophysiology with great expectations for translational applications, including regenerative medicine...
February 19, 2016: Journal of Biological Chemistry
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