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https://www.readbyqxmd.com/read/28615312/stem-cells-in-repair-of-gastrointestinal-epithelia
#1
REVIEW
Amanda Andersson-Rolf, Matthias Zilbauer, Bon-Kyoung Koo, Hans Clevers
Among the endodermal tissues of adult mammals, the gastrointestinal (GI) epithelium exhibits the highest turnover rate. As the ingested food moves along the GI tract, gastric acid, digestive enzymes, and gut resident microbes aid digestion as well as nutrient and mineral absorption. Due to the harsh luminal environment, replenishment of new epithelial cells is essential to maintain organ structure and function during routine turnover and injury repair. Tissue-specific adult stem cells in the GI tract serve as a continuous source for this immense regenerative activity...
July 2017: Physiology
https://www.readbyqxmd.com/read/28600348/loss-of-the-wnt-receptor-frizzled7-in-the-gastric-epithelium-is-deleterious-and-triggers-rapid-repopulation-in-vivo
#2
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/28575679/wnt-%C3%AE-catenin-signaling-disease-and-emerging-therapeutic-modalities
#3
REVIEW
Roel Nusse, Hans Clevers
The WNT signal transduction cascade is a main regulator of development throughout the animal kingdom. Wnts are also key drivers of most types of tissue stem cells in adult mammals. Unsurprisingly, mutated Wnt pathway components are causative to multiple growth-related pathologies and to cancer. Here, we describe the core Wnt/β-catenin signaling pathway, how it controls stem cells, and contributes to disease. Finally, we discuss strategies for Wnt-based therapies.
June 1, 2017: Cell
https://www.readbyqxmd.com/read/28526587/wnt-%C3%AE-catenin-signaling-in-adult-mammalian-epithelial-stem-cells
#4
REVIEW
Kai Kretzschmar, Hans Clevers
Adult stem cells self-renew and replenish differentiated cells in various organs and tissues throughout a mammal's life. Over the last 25 years an ever-growing body of knowledge has unraveled the essential regulation of adult mammalian epithelia by the canonical Wnt signaling with its key intracellular effector β-catenin. In this review, we discuss the principles of the signaling pathway and its role in adult epithelial stem cells of the intestine and skin during homeostasis and tumorigenesis. We further highlight the research that led to the identification of new stem cell markers and methods to study adult stem cells ex vivo...
May 17, 2017: Developmental Biology
https://www.readbyqxmd.com/read/28522527/lineage-dependent-spatial-and-functional-organization-of-the-mammalian-enteric-nervous-system
#5
Reena Lasrado, Werend Boesmans, Jens Kleinjung, Carmen Pin, Donald Bell, Leena Bhaw, Sarah McCallum, Hui Zong, Liqun Luo, Hans Clevers, Pieter Vanden Berghe, Vassilis Pachnis
The enteric nervous system (ENS) is essential for digestive function and gut homeostasis. Here we show that the amorphous neuroglia networks of the mouse ENS are composed of overlapping clonal units founded by postmigratory neural crest-derived progenitors. The spatial configuration of ENS clones depends on proliferation-driven local interactions of ENS progenitors with lineally unrelated neuroectodermal cells, the ordered colonization of the serosa-mucosa axis by clonal descendants, and gut expansion. Single-cell transcriptomics and mutagenesis analysis delineated dynamic molecular states of ENS progenitors and identified RET as a regulator of neurogenic commitment...
May 19, 2017: Science
https://www.readbyqxmd.com/read/28512141/oncogene-inducible-organoids-as-a-miniature-platform-to-assess-cancer-characteristics
#6
Tomohiro Mizutani, Yoshiyuki Tsukamoto, Hans Clevers
Direct effects of oncogenic proteins or inhibitor treatments on signaling pathways are difficult to assess in transgenic mice. In this issue, Riemer et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201610058) demonstrate that oncogene-inducible organoids offer the experimental versatility of two-dimensional cell lines, while closely representing the in vivo situation.
June 5, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28506535/sca-1-expression-level-identifies-quiescent-hematopoietic-stem-and-progenitor-cells
#7
Mina N F Morcos, Kristina B Schoedel, Anja Hoppe, Rayk Behrendt, Onur Basak, Hans C Clevers, Axel Roers, Alexander Gerbaulet
Blood cell generation depends on continuous cellular output by the sequential hierarchy of hematopoietic stem cell (HSC) and progenitor populations that all contain quiescent and actively cycling cells. Hematopoietic stem and progenitor cells (HSPCs) express the surface molecule Stem cell antigen 1 (SCA-1/LY6A). Using histone 2B-red fluorescent fusion protein label retention and cell-cycle reporter mice, we demonstrate that high SCA-1 expression (SCA-1(hi)) identifies not only quiescent HSCs but quiescent cells on all hierarchical levels within the lineage(-)SCA-1(+)KIT(+) (LSK) population...
June 6, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28475124/goblet-cells-contribute-to-ocular-surface-immune-tolerance-implications-for-dry-eye-disease
#8
Flavia L Barbosa, Yangyan Xiao, Fang Bian, Terry G Coursey, Byung Yi Ko, Hans Clevers, Cintia S de Paiva, Stephen C Pflugfelder
Conjunctival goblet cell (GC) loss in dry eye is associated with ocular surface inflammation. This study investigated if conjunctival GCs contribute to ocular surface immune tolerance. Antigens applied to the ocular surface, imaged by confocal microscopy, passed into the conjunctival stroma through goblet cell associated passages (GAPs) in wild type C57BL/6 (WT), while ovalbumin (OVA) was retained in the epithelium of SAM pointed domain containing ETS transcription factor (Spdef) knockout mice (Spdef(-)/(-)) that lack GCs and are a novel model of dry eye...
May 5, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28467818/surrogate-wnt-agonists-that-phenocopy-canonical-wnt-and-%C3%AE-catenin-signalling
#9
Claudia Y Janda, Luke T Dang, Changjiang You, Junlei Chang, Wim de Lau, Zhendong A Zhong, Kelley S Yan, Owen Marecic, Dirk Siepe, Xingnan Li, James D Moody, Bart O Williams, Hans Clevers, Jacob Piehler, David Baker, Calvin J Kuo, K Christopher Garcia
Wnt proteins modulate cell proliferation and differentiation and the self-renewal of stem cells by inducing β-catenin-dependent signalling through the Wnt receptor frizzled (FZD) and the co-receptors LRP5 and LRP6 to regulate cell fate decisions and the growth and repair of several tissues. The 19 mammalian Wnt proteins are cross-reactive with the 10 FZD receptors, and this has complicated the attribution of distinct biological functions to specific FZD and Wnt subtype interactions. Furthermore, Wnt proteins are modified post-translationally by palmitoylation, which is essential for their secretion, function and interaction with FZD receptors...
May 11, 2017: Nature
https://www.readbyqxmd.com/read/28429766/beyond-growth-signaling-paneth-cells-metabolically-suppport-iscs
#10
Talya L Dayton, Hans Clevers
Single Lgr5 intestinal stem cells (ISCs) can be expanded in vitro into epithelial organoids or "mini-guts", self-organizing cellular structures that recreate the intestinal differentiation program; Paneth cells, which constitute the intestinal stem cell niche, secrete stem cell growth signals, and are thus essential for this process. In a recent paper published in Nature, Rodríguez-Colman et al. describe how Paneth cells may be supporting the metabolic state of ISCs.
April 21, 2017: Cell Research
https://www.readbyqxmd.com/read/28391362/stem-cell-derived-organoids-and-their-application-for-medical-research-and-patient-treatment
#11
REVIEW
Sina Bartfeld, Hans Clevers
3D culture has allowed the initiation and expansion of organ-like structures, called organoids, from either tissue-resident adult stem cells or pluripotent stem cells. Today, organoids can be grown to resemble a wide variety of organs, exhibiting remarkable similarity to their in vivo counterparts. As successful organoid generation is possible from virtually every patient, organoids hold a great promise for medical research and the development of new treatments. They have already found their way into the clinic, enabling personalized medicine in small patient trials...
April 8, 2017: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://www.readbyqxmd.com/read/28381597/waging-war-against-pancreatic-cancer-an-interview-with-david-tuveson
#12
David Tuveson
David Tuveson, Director of the Cancer Center at Cold Spring Harbor Laboratory, is a clinician-scientist with a longstanding interest in understanding and treating pancreatic cancer. Since developing the first mouse model of pancreatic cancer in 2002, the Tuveson lab has made a series of discoveries that shed light on the molecular drivers of this disease and provide promising therapeutic avenues for a malignancy that is notoriously challenging to treat. In collaboration with Hans Clevers, David developed the first pancreatic cancer organoids, which revolutionized the field by providing a powerful model system for basic discoveries and advancement of personalized medicine...
April 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28344000/long-term-adult-feline-liver-organoid-cultures-for-disease-modeling-of%C3%A2-hepatic-steatosis
#13
Hedwig S Kruitwagen, Loes A Oosterhoff, Ingrid G W H Vernooij, Ingrid M Schrall, Monique E van Wolferen, Farah Bannink, Camille Roesch, Lisa van Uden, Martijn R Molenaar, J Bernd Helms, Guy C M Grinwis, Monique M A Verstegen, Luc J W van der Laan, Meritxell Huch, Niels Geijsen, Robert G Vries, Hans Clevers, Jan Rothuizen, Baukje A Schotanus, Louis C Penning, Bart Spee
Hepatic steatosis is a highly prevalent liver disease, yet research is hampered by the lack of tractable cellular and animal models. Steatosis also occurs in cats, where it can cause severe hepatic failure. Previous studies demonstrate the potential of liver organoids for modeling genetic diseases. To examine the possibility of using organoids to model steatosis, we established a long-term feline liver organoid culture with adult liver stem cell characteristics and differentiation potential toward hepatocyte-like cells...
April 11, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28341301/disease-modeling-in-stem-cell-derived-3d-organoid-systems
#14
REVIEW
Devanjali Dutta, Inha Heo, Hans Clevers
Organoids are 3D in vitro culture systems derived from self-organizing stem cells. They can recapitulate the in vivo architecture, functionality, and genetic signature of original tissues. Thus, organoid technology has been rapidly applied to understanding stem cell biology, organogenesis, and various human pathologies. The recent development of human patient-derived organoids has enabled disease modeling with precision, highlighting their great potential in biomedical applications, translational medicine, and personalized therapy...
March 21, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28298434/everything-has-its-time-id2-clocks-embryonic-specification-of-lgr5-gut-stem-cells
#15
Kai Kretzschmar, Hans Clevers
No abstract text is available yet for this article.
April 3, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28292848/intestinal-epithelial-organoids-fuse-to-form-self-organizing-tubes-in-floating-collagen-gels
#16
Norman Sachs, Yoshiyuki Tsukamoto, Pekka Kujala, Peter J Peters, Hans Clevers
Multiple recent examples highlight how stem cells can self-organize in vitro to establish organoids that closely resemble their in vivo counterparts. Single Lgr5(+) mouse intestinal stem cells can be cultured under defined conditions forming ever-expanding epithelial organoids that retain cell polarization, cell type diversity and anatomical organization of the in vivo epithelium. Although exhibiting a remarkable level of self-organization, the so called 'mini-guts' have a closed cystic structure of microscopic size...
March 15, 2017: Development
https://www.readbyqxmd.com/read/28292843/translational-applications-of-adult-stem-cell-derived-organoids
#17
REVIEW
Jarno Drost, Hans Clevers
Adult stem cells from a variety of organs can be expanded long-term in vitro as three-dimensional organotypic structures termed organoids. These adult stem cell-derived organoids retain their organ identity and remain genetically stable over long periods of time. The ability to grow organoids from patient-derived healthy and diseased tissue allows for the study of organ development, tissue homeostasis and disease. In this Review, we discuss the generation of adult stem cell-derived organoid cultures and their applications in in vitro disease modeling, personalized cancer therapy and regenerative medicine...
March 15, 2017: Development
https://www.readbyqxmd.com/read/28287550/forskolin-induced-swelling-in-intestinal-organoids-an-in-vitro-assay-for-assessing-drug-response-in-cystic-fibrosis-patients
#18
Sylvia F Boj, Annelotte M Vonk, Marvin Statia, Jinyi Su, Robert R G Vries, Jeffrey M Beekman, Hans Clevers
Recently-developed cystic fibrosis transmembrane conductance regulator (CFTR)-modulating drugs correct surface expression and/or function of the mutant CFTR channel in subjects with cystic fibrosis (CF). Identification of subjects that may benefit from these drugs is challenging because of the extensive heterogeneity of CFTR mutations, as well as other unknown factors that contribute to individual drug efficacy. Here, we describe a simple and relatively rapid assay for measuring individual CFTR function and response to CFTR modulators in vitro...
February 11, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28270604/genetic-dissection-of-colorectal-cancer-progression-by-orthotopic-transplantation-of-engineered-cancer-organoids
#19
Arianna Fumagalli, Jarno Drost, Saskia J E Suijkerbuijk, Ruben van Boxtel, Joep de Ligt, G Johan Offerhaus, Harry Begthel, Evelyne Beerling, Ee Hong Tan, Owen J Sansom, Edwin Cuppen, Hans Clevers, Jacco van Rheenen
In the adenoma-carcinoma sequence, it is proposed that intestinal polyps evolve through a set of defined mutations toward metastatic colorectal cancer (CRC). Here, we dissect this adenoma-carcinoma sequence in vivo by using an orthotopic organoid transplantation model of human colon organoids engineered to harbor different CRC mutation combinations. We demonstrate that sequential accumulation of oncogenic mutations in Wnt, EGFR, P53, and TGF-β signaling pathways facilitates efficient tumor growth, migration, and metastatic colonization...
March 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28262686/lipid-mediated-wnt-protein-stabilization-enables-serum-free-culture-of-human-organ-stem-cells
#20
Nesrin Tüysüz, Louis van Bloois, Stieneke van den Brink, Harry Begthel, Monique M A Verstegen, Luis J Cruz, Lijian Hui, Luc J W van der Laan, Jeroen de Jonge, Robert Vries, Eric Braakman, Enrico Mastrobattista, Jan J Cornelissen, Hans Clevers, Derk Ten Berge
Wnt signalling proteins are essential for culture of human organ stem cells in organoids, but most Wnt protein formulations are poorly active in serum-free media. Here we show that purified Wnt3a protein is ineffective because it rapidly loses activity in culture media due to its hydrophobic nature, and its solubilization requires a detergent, CHAPS (3-[(3-cholamidopropyl) dimethylammonio]-1-propanesulfonate), that interferes with stem cell self-renewal. By stabilizing the Wnt3a protein using phospholipids and cholesterol as carriers, we address both problems: Wnt activity remains stable in serum-free media, while non-toxic carriers allow the use of high Wnt concentrations...
March 6, 2017: Nature Communications
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