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https://www.readbyqxmd.com/read/28100467/an-essential-role-of-cbl-and-cbl-b-ubiquitin-ligases-in-mammary-stem-cell-maintenance
#1
Bhopal Mohapatra, Neha Zutshi, Wei An, Benjamin Goetz, Priyanka Arya, Timothy A Bielecki, Insha Mustaq, Matthew D Storck, Jane L Meza, Vimla Band, Hamid Band
CBL and CBL-B ubiquitin ligases are negative regulators of tyrosine kinase signaling with established roles in the immune system. However, their physiological roles in epithelial tissues are unknown. Here we used the MMTV-Cre-mediated Cbl gene deletion on a Cbl-b-null background as well as a tamoxifen-inducible mammary stem cell (MaSC)-specific Cbl/Cbl-b double knockout (DKO), using Lgr5-GFP-CreERT, to demonstrate a mammary epithelial cell-autonomous requirement of CBL and CBL-B in the maintenance of MaSCs...
January 18, 2017: Development
https://www.readbyqxmd.com/read/28092415/the-cluster-micrornas-mir-194-and-mir-215-suppress-the-tumorigenicity-of-intestinal-tumor-organoids
#2
Toshiaki Nakaoka, Yoshimasa Saito, Yuriko Shimamoto, Toshihide Muramatsu, Masaki Kimura, Yae Kanai, Hidetsugu Saito
Tumor stem cells with self-renewal and multipotent capacity play critical roles in the initiation and progression of cancer. Recently, a new 3D culture system known as organoid culture has been developed, allowing Lgr5-positive stem cells to form organoids that resemble the properties of original tissues. Here we established organoids derived from intestinal tumors of Apc(min/+) mice and normal intestinal epithelia of C57BL/6J mice and investigated the roles of microRNAs (miRNAs) in intestinal tumor organoids...
January 16, 2017: Cancer Science
https://www.readbyqxmd.com/read/28078320/lgr4-and-lgr5-function-redundantly-during-human-endoderm-differentiation
#3
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/28077488/id2-controls-specification-of-lgr5-intestinal-stem-cell-progenitors-during-gut-development
#4
Lira Nigmatullina, Maxim Norkin, Margarita M Dzama, Berith Messner, Sergi Sayols, Natalia Soshnikova
The adult intestinal stem cells (ISCs), their hierarchies, mechanisms of maintenance and differentiation have been extensively studied. However, when and how ISCs are established during embryogenesis remains unknown. We show here that the transcription regulator Id2 controls the specification of embryonic Lgr5(+) progenitors in the developing murine small intestine. Cell fate mapping analysis revealed that Lgr5(+) progenitors emerge at E13.5 in wild-type embryos and differ from the rest on the intestinal epithelium by a characteristic ISC signature...
January 11, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28074039/cd34-mesenchymal-cells-are-a-major-component-of-the-intestinal-stem-cells-niche-at-homeostasis-and-after-injury
#5
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...
10, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28070642/distinct-expression-profile-of-stem-cell-markers-lgr5-and-lgr6-in-basaloid-skin-tumors
#6
Bo Gun Jang, Cheol Lee, Hye Sung Kim, Myung Soo Shin, Min Seok Cheon, Jae Wang Kim, Woo Ho Kim
Mammalian epidermis, which is composed of hair follicles, sebaceous glands, and interfollicular epidermis, is maintained by discrete stem cells. In vivo lineage tracing demonstrated that murine LGR5 cells are mainly responsible for hair follicle regeneration whereas LGR6 cells generate sebaceous glands and interfollicular epidermis. However, little is known about their expression in the human skin tumors. In this study, we investigated the expression profile of LGR5 and LGR6 in a variety of human skin tumors including basaloid tumors with follicular differentiation (94 basal cell carcinomas, 18 trichoepitheliomas, 3 basaloid follicular hamartomas, and 12 pilomatricomas) and tumors with ductal differentiation (7 eccrine poromas, 8 hidradenomas, and 5 spiradenomas)...
January 9, 2017: Virchows Archiv: An International Journal of Pathology
https://www.readbyqxmd.com/read/28059064/bmp-restricts-stemness-of-intestinal-lgr5-stem-cells-by-directly-suppressing-their-signature-genes
#7
Zhen Qi, Yehua Li, Bing Zhao, Chi Xu, Yuan Liu, Haonan Li, Bingjie Zhang, Xinquan Wang, Xiao Yang, Wei Xie, Baojie Li, Jing-Dong Jackie Han, Ye-Guang Chen
The intestinal epithelium possesses a remarkable self-renewal ability, which is mediated by actively proliferating Lgr5(+) stem cells. Bone morphogenetic protein (BMP) signalling represents one major counterforce that limits the hyperproliferation of intestinal epithelium, but the exact mechanism remains elusive. Here we demonstrate that epithelial BMP signalling plays an indispensable role in restricting Lgr5(+) stem cell expansion to maintain intestinal homeostasis and prevent premalignant hyperproliferation on damage...
January 6, 2017: Nature Communications
https://www.readbyqxmd.com/read/28053963/expression-of-leucine-rich-repeat-containing-g-protein-coupled-receptor-5-and-cd44-potential-implications-for-gastric-cancer-stem-cell-marker
#8
Yoon Jin Choi, Nayoung Kim, Hye Seung Lee, Seon Mee Park, Ji Hyun Park, Hyuk Yoon, Cheol Min Shin, Young Soo Park, Jin-Wook Kim, Dong Ho Lee
BACKGROUND: The human leucine-rich repeat-containing G-protein coupled receptor (LGR) 5 and CD44 are one of the candidates for the marker of gastric cancer stem cells. We compared the expressions of two genes among control, dysplasia and cancer groups. METHODS: We compared the mRNA expression of LGR5, CD44 and CD44v8-10 and immunohistochemistry (IHC) of LGR5 and CD44 in gastric antral mucosa of 45 controls, 36 patients with gastric dysplasia, and 39 patients with early gastric cancer...
December 2016: Journal of Cancer Prevention
https://www.readbyqxmd.com/read/28053090/functional-transcriptomics-in-diverse-intestinal-epithelial-cell-types-reveals-robust-microrna-sensitivity-in-intestinal-stem-cells-to-microbial-status
#9
Bailey C E Peck, Amanda T Mah, Wendy A Pitman, Shengli Ding, P Kay Lund, Praveen Sethupathy
Gut microbiota play an important role in regulating the development of the host immune system, metabolic rate, and at times, disease pathogenesis. The factors and mechanisms that mediate interactions between microbiota and the intestinal epithelium are not fully understood. We provide novel evidence that microbiota may control intestinal epithelial stem cell (IESC) proliferation in part through microRNAs (miRNAs). We demonstrate that miRNA profiles differ dramatically across functionally distinct cell types of the mouse jejunal intestinal epithelium and that miRNAs respond to microbiota in a highly cell-type specific manner...
January 4, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28043948/angptl2-expression-in-the-intestinal-stem-cell-niche-controls-epithelial-regeneration-and-homeostasis
#10
Haruki Horiguchi, Motoyoshi Endo, Kohki Kawane, Tsuyoshi Kadomatsu, Kazutoyo Terada, Jun Morinaga, Kimi Araki, Keishi Miyata, Yuichi Oike
The intestinal epithelium continually self-renews and can rapidly regenerate after damage. Dysregulation of intestinal epithelial homeostasis leads to severe inflammatory bowel disease. Additionally, aberrant signaling by the secreted protein angiopoietin-like protein 2 (ANGPTL2) causes chronic inflammation in a variety of diseases. However, little is known about the physiologic role of ANGPTL2 in normal tissue homeostasis and during wound repair following injury. Here, we assessed ANGPTL2 function in intestinal physiology and disease in vivo Although intestinal development proceeded normally in Angptl2-deficient mice, expression levels of the intestinal stem cell (ISC) marker gene Lgr5 decreased, which was associated with decreased transcriptional activity of β-catenin in Angptl2-deficient mice...
January 2, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28013222/generation-and-characterization-of-monoclonal-antibodies-against-human-lgr6
#11
Shin-Ichi Funahashi, Yasunori Suzuki, Kiyotaka Nakano, Shigeto Kawai, Masami Suzuki
Leucine-rich repeat-containing G protein-coupled receptor 6 (LGR6) is a seven-pass transmembrane protein known to be a marker of stem cells in several organs. To deepen our understanding of the cell biology of LGR6-positive cells, including stem cells, we generated monoclonal antibodies (mAbs) against human LGR6. DNA immunization followed by whole-cell immunization with LGR6-expressing transfectants was performed to obtain mAbs that recognized the native form of LGR6. Hybridomas were screened by flow cytometry using LGR6-transfected cells...
December 24, 2016: Journal of Biochemistry
https://www.readbyqxmd.com/read/27983919/overexpression-of-per3-inhibits-self-renewal-capability-and-chemoresistance-of-colorectal-cancer-stem-like-cells-via-inhibition-of-notch-and-%C3%AE-catenin-signaling
#12
Feng Zhang, Hong Sun, Sai Zhang, Xin Yang, Guogang Zhang, Tao Su
PER3, a circadian clock gene, plays an important role in colorectal cancer, but its action and underlying mechanisms incolorectal cancer stem-like cells (CSCs) remain unclear. Here, the colorectal CSCs were enriched in colorectal HCT-116 sphere-forming cells, expressing lower levels of stem cell markers CD133, CD44, LGR5, Sox2 compared with HCT-116 cells. And drug-resistant strain from HCT-116 was established. Western blot and qRT-PCR analysis showed that PER3 was downregulated in colorectal CSCs and drug-resistant HCT-116...
October 26, 2016: Oncology Research
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
#13
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/27939883/indispensable-role-of-notch-ligand-dependent-signaling-in-the-proliferation-and-stem-cell-niche-maintenance-of-apc-deficient-intestinal-tumors
#14
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...
January 22, 2017: 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
#15
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/27919339/the-role-of-gene-mutations-and-gene-products-in-intestinal-tissue-reactions-from-ionising-radiation
#16
Jolyon H Hendry, Kensuke Otsuka
The response of the intestine to (low linear-energy-transfer) ionising radiation is reviewed regarding the cellular basis to the reactions, the regenerative processes which restore the tissue, and external agents which aid its recovery. In the steady-state, it is generally considered that the crypt cell lineages in both small and large intestine are maintained by a small number of stem cells, but there are differences for example in the composition of their niche residence and in the numbers of transit cell generations...
October 2016: Mutation Research
https://www.readbyqxmd.com/read/27913042/objective-analysis-of-cancer-stem-cell-marker-expression-using-immunohistochemistry
#17
T J Miller, M J McCoy, C Hemmings, M K Bulsara, B Iacopetta, C F Platell
Analysis of immunohistochemical expression is often a subjective and semiquantitative process that can lead to the inconsistent reporting of results. To assess the effect that region selection and quantification method have on results, five different cancer stem cell markers were used in this study to compare tissue scoring with digital analysis methods that used three different tissue annotation methods. Samples of tumour and normal mucosa were used from 10 consecutive stage II colon cancer patients and stained for the putative cancer stem cell markers ALDH1, CD44v6, CD133, Lgr5 and SOX2...
January 2017: Pathology
https://www.readbyqxmd.com/read/27887719/leucine-rich-repeat-containing-g-protein-coupled%C3%A2-receptor%C3%A2-5-positive%C3%A2-cells%C3%A2-in-the-endometrial-stem-cell-niche
#18
Irene Cervelló, Claudia Gil-Sanchis, Xavier Santamaría, Amparo Faus, Julia Vallvé-Juanico, Patricia Díaz-Gimeno, Oriana Genolet, Antonio Pellicer, Carlos Simón
OBJECTIVE: To study, isolate and characterize leucine-rich repeat-containing heterotrimeric guanine nucleotide-binding protein-coupled receptor 5 (LGR5)-positive cells from human endometrium to determine their functional relevance. DESIGN: Prospective experimental animal study. SETTING: University research laboratories. ANIMAL(S): Nonobese diabetic mice (NOD-SCID) (strain code 394; NOD.CB17-Prkdc(scid)/NcrCrl). INTERVENTION(S): Human LGR5(+) cells were labeled with superparamagnetic iron oxide nanoparticles (SPIOs) and injected under the kidney capsule in immunocompromised mice...
November 22, 2016: Fertility and Sterility
https://www.readbyqxmd.com/read/27881008/mir-33a-expression-sensitizes-lgr5-hcc-cscs-to-doxorubicin-via-abca1
#19
H Hou, Y Kang, Y Li, Y Zheng, G Ding, J Shang
Cancer stem cells (CSCs) are responsible for the unrestrained cell growth and chemo-resistance of malignant tumors. Reports about miR-33a in different type of cancer are limited, and it remains elusive whether there is a link between miR-33a and chemo-resistance of CSCs. Here we report that Lgr5+ hepatocellular carcinoma (HCC) cells from primary tissues and cell lines behave similarly to CSCs and are chemo-resistant to doxorubicin. Significantly, reduced miR-33a expression is associated with the chemo-resistance of Lgr5+ HCC-CSCs, accompanied by an overexpression of ABCA1 which is identified as target of miR-33a by mainly using miRNA luciferase assay and western-blotting...
November 24, 2016: Neoplasma
https://www.readbyqxmd.com/read/27880730/loss-of-zg16-is-regulated-by-mir-196a-and-contributes-to-stemness-and-progression-of-colorectal-cancer
#20
Xiaobing Chen, Peng Du, Junjun She, Liang Cao, Yingchao Li, Hongping Xia
Colorectal cancer (CRC) is one of the most common malignant tumour and the leading cause of cancer-related mortality worldwide. Clarification of the mechanism that underlies CRC tumorigenesis and progression therefore is urgently needed ffor developing novel therapies. Through analysis of The Cancer Genome Atlas (TCGA) dataset, we identified an interesting gene, ZG16, which is significantly decreased in CRC samples compared to adjacent non-tumor tissues and associated with prognosis of patients. We found that the expression of ZG16 correlated with CRC related genes which were regulated by APC/CTNNB1 pathway...
November 17, 2016: Oncotarget
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