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https://www.readbyqxmd.com/read/28298434/everything-has-its-time-id2-clocks-embryonic-specification-of-lgr5-gut-stem-cells
#1
Kai Kretzschmar, Hans Clevers
No abstract text is available yet for this article.
March 15, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28292848/intestinal-epithelial-organoids-fuse-to-form-self-organizing-tubes-in-floating-collagen-gels
#2
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
#3
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
#4
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
#5
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 7, 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
#6
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
https://www.readbyqxmd.com/read/28244067/wnt-signaling-events-near-the-cell-membrane-and-their-pharmacological-targeting-for-the-treatment-of-cancer
#7
REVIEW
Else Driehuis, Hans Clevers
WNT signaling is an essential signaling pathway for all multicellular animals. Although first described more than thirty years ago, new components and regulators of the pathway are still being discovered. Considering its importance in both embryonic development and adult homeostasis, it is not surprising that this pathway is often deregulated in human diseases such as cancer. Recently, it became clear that in addition to cytoplasmic components such as β-catenin, also membrane-bound or extracellular components of the WNT pathway are often altered in cancer...
February 28, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28219675/tcf7l2-plays-crucial-roles-in-forebrain-development-through-regulation-of-thalamic-and-habenular-neuron-identity-and-connectivity
#8
Myungsin Lee, Jiyeon Yoon, Hobeom Song, Bumwhee Lee, Duc Tri Lam, Jaeseung Yoon, Kwanghee Baek, Hans Clevers, Yongsu Jeong
The thalamus acts as a central integrator for processing and relaying sensory and motor information to and from the cerebral cortex, and the habenula plays pivotal roles in emotive decision making by modulating dopaminergic and serotonergic circuits. These neural compartments are derived from a common developmental progenitor domain, called prosomere 2, in the caudal forebrain. Thalamic and habenular neurons exhibit distinct molecular profile, neurochemical identity, and axonal circuitry. However, the mechanisms of how their progenitors in prosomere 2 give rise to these two populations of neurons and contribute to the forebrain circuitry remains unclear...
April 1, 2017: Developmental Biology
https://www.readbyqxmd.com/read/28211365/converging-biofabrication-and-organoid-technologies-the-next-frontier-in-hepatic-and-intestinal-tissue-engineering
#9
Kerstin Schneeberger, Bart Spee, Pedro Costa, Norman Sachs, Hans Clevers, Jos Malda
Adult tissue stem cells can form self-organizing 3D organoids in vitro. Organoids resemble small units of their organ of origin and have great potential for tissue engineering, as well as models of disease. However, current culture technology limits the size, architecture and complexity of organoids. Here, we review the establishment of intestinal and hepatic organoids and discuss how the convergence of organoids and biofabrication technologies can help overcome current limitations, and thereby further advance the translational application of organoids in tissue engineering and regenerative medicine...
March 6, 2017: Biofabrication
https://www.readbyqxmd.com/read/28170393/correction-the-leukemia-associated-mllt10-af10-dot1l-are-tcf4-%C3%AE-catenin-coactivators-essential-for-intestinal-homeostasis
#10
Tokameh Mahmoudi, Sylvia F Boj, Pantelis Hatzis, Vivian S W Li, Nadia Taouatas, Robert G J Vries, Hans Teunissen, Harry Begthel, Jeroen Korving, Shabaz Mohammed, Albert J R Heck, Hans Clevers
[This corrects the article DOI: 10.1371/journal.pbio.1000539.].
February 2017: PLoS Biology
https://www.readbyqxmd.com/read/28126704/crispr-cas-9-genome-editing-and-its-applications-in-organoids
#11
Else Driehuis, Hans Clevers
Organoids are 3D structures derived from adult or embryonic stem cells that maintain many structural and functional features of their respective organ. Recently, genome editing based on the bacterial defense mechanism CRISPR/Cas9 has emerged as an easily applicable and reliable lab tool. Combining organoids and CRISPR/Cas9 creates exciting new opportunities to study organ development and human disease in vitro. The potential applications of CRISPR in organoids are only beginning to be explored.
January 26, 2017: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/28104906/interrogating-open-issues-in-cancer-precision-medicine-with-patient-derived-xenografts
#12
REVIEW
Annette T Byrne, Denis G Alférez, Frédéric Amant, Daniela Annibali, Joaquín Arribas, Andrew V Biankin, Alejandra Bruna, Eva Budinská, Carlos Caldas, David K Chang, Robert B Clarke, Hans Clevers, George Coukos, Virginie Dangles-Marie, S Gail Eckhardt, Eva Gonzalez-Suarez, Els Hermans, Manuel Hidalgo, Monika A Jarzabek, Steven de Jong, Jos Jonkers, Kristel Kemper, Luisa Lanfrancone, Gunhild Mari Mælandsmo, Elisabetta Marangoni, Jean-Christophe Marine, Enzo Medico, Jens Henrik Norum, Héctor G Palmer, Daniel S Peeper, Pier Giuseppe Pelicci, Alejandro Piris-Gimenez, Sergio Roman-Roman, Oscar M Rueda, Joan Seoane, Violeta Serra, Laura Soucek, Dominique Vanhecke, Alberto Villanueva, Emilie Vinolo, Andrea Bertotti, Livio Trusolino
Patient-derived xenografts (PDXs) have emerged as an important platform to elucidate new treatments and biomarkers in oncology. PDX models are used to address clinically relevant questions, including the contribution of tumour heterogeneity to therapeutic responsiveness, the patterns of cancer evolutionary dynamics during tumour progression and under drug pressure, and the mechanisms of resistance to treatment. The ability of PDX models to predict clinical outcomes is being improved through mouse humanization strategies and the implementation of co-clinical trials, within which patients and PDXs reciprocally inform therapeutic decisions...
April 2017: Nature Reviews. Cancer
https://www.readbyqxmd.com/read/28104841/human-tissues-in-a-dish-the-research-and-ethical-implications-of-organoid-technology
#13
REVIEW
Annelien L Bredenoord, Hans Clevers, Juergen A Knoblich
The ability to generate human tissues in vitro from stem cells has raised enormous expectations among the biomedical research community, patients, and the general public. These organoids enable studies of normal development and disease and allow the testing of compounds directly on human tissue. Organoids hold the promise to influence the entire innovation cycle in biomedical research. They affect fields that have been subjects of intense ethical debate, ranging from animal experiments and the use of embryonic or fetal human tissues to precision medicine, organoid transplantation, and gene therapy...
January 20, 2017: Science
https://www.readbyqxmd.com/read/28102212/erratum-programs-for-the-persistence-vigilance-and-control-of-human-cd8-lung-resident-memory-t-cells
#14
Pleun Hombrink, Christina Helbig, Ronald A Backer, Berber Piet, Anna E Oja, Regina Stark, Giso Brasser, Aldo Jongejan, René E Jonkers, Benjamin Nota, Onur Basak, Hans C Clevers, Perry D Moerland, Derk Amsen, René A W van Lier
No abstract text is available yet for this article.
January 19, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28052255/personalized-proteome-profiles-of-healthy-and-tumor-human-colon-organoids-reveal-both-individual-diversity-and-basic-features-of-colorectal-cancer
#15
Alba Cristobal, Henk W P van den Toorn, Marc van de Wetering, Hans Clevers, Albert J R Heck, Shabaz Mohammed
Diseases at the molecular level are complex and patient dependent, necessitating development of strategies that enable precision treatment to optimize clinical outcomes. Organoid technology has recently been shown to have the potential to recapitulate the in vivo characteristics of the original individual's tissue in a three-dimensional in vitro culture system. Here, we present a quantitative mass-spectrometry-based proteomic analysis and a comparative transcriptomic analysis of human colorectal tumor and healthy organoids derived, in parallel, from seven patients...
January 3, 2017: Cell Reports
https://www.readbyqxmd.com/read/28040417/i%C3%AE%C2%BAbns-enhances-t-follicular-helper-cell-differentiation-and-function-as-downstream-of-ascl2
#16
Junichi Hosokawa, Kotaro Suzuki, Kazuyuki Meguro, Shigeru Tanaka, Yuko Maezawa, Akira Suto, Lisa Fujimura, Akemi Sakamoto, Hans Clevers, Osamu Ohara, Hiroshi Nakajima
IκBNS plays an important role in Tfh cell differentiation and function.
December 28, 2016: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28028233/aberrantly-expressed-lgr4-empowers-wnt-signaling-in-multiple-myeloma-by-hijacking-osteoblast-derived-r-spondins
#17
Harmen van Andel, Zemin Ren, Iris Koopmans, Sander P J Joosten, Kinga A Kocemba, Wim de Lau, Marie José Kersten, Alexander M de Bruin, Jeroen E J Guikema, Hans Clevers, Marcel Spaargaren, Steven T Pals
The unrestrained growth of tumor cells is generally attributed to mutations in essential growth control genes, but tumor cells are also affected by, or even addicted to, signals from the microenvironment. As therapeutic targets, these extrinsic signals may be equally significant as mutated oncogenes. In multiple myeloma (MM), a plasma cell malignancy, most tumors display hallmarks of active Wnt signaling but lack activating Wnt-pathway mutations, suggesting activation by autocrine Wnt ligands and/or paracrine Wnts emanating from the bone marrow (BM) niche...
January 10, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27939219/induced-quiescence-of-lgr5-stem-cells-in-intestinal-organoids-enables-differentiation-of-hormone-producing-enteroendocrine-cells
#18
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...
February 2, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/27869803/genome-wide-crispr-screens-reveal-a-wnt-fzd5-signaling-circuit-as-a-druggable-vulnerability-of-rnf43-mutant-pancreatic-tumors
#19
Zachary Steinhart, Zvezdan Pavlovic, Megha Chandrashekhar, Traver Hart, Xiaowei Wang, Xiaoyu Zhang, Mélanie Robitaille, Kevin R Brown, Sridevi Jaksani, René Overmeer, Sylvia F Boj, Jarrett Adams, James Pan, Hans Clevers, Sachdev Sidhu, Jason Moffat, Stéphane Angers
Forward genetic screens with CRISPR-Cas9 genome editing enable high-resolution detection of genetic vulnerabilities in cancer cells. We conducted genome-wide CRISPR-Cas9 screens in RNF43-mutant pancreatic ductal adenocarcinoma (PDAC) cells, which rely on Wnt signaling for proliferation. Through these screens, we discovered a unique requirement for a Wnt signaling circuit: engaging FZD5, one of the ten Frizzled receptors encoded in the human genome. Our results uncover an underappreciated level of context-dependent specificity at the Wnt receptor level...
January 2017: Nature Medicine
https://www.readbyqxmd.com/read/27851739/designer-matrices-for-intestinal-stem-cell-and-organoid-culture
#20
Nikolce Gjorevski, Norman Sachs, Andrea Manfrin, Sonja Giger, Maiia E Bragina, Paloma Ordóñez-Morán, Hans Clevers, Matthias P Lutolf
Epithelial organoids recapitulate multiple aspects of real organs, making them promising models of organ development, function and disease. However, the full potential of organoids in research and therapy has remained unrealized, owing to the poorly defined animal-derived matrices in which they are grown. Here we used modular synthetic hydrogel networks to define the key extracellular matrix (ECM) parameters that govern intestinal stem cell (ISC) expansion and organoid formation, and show that separate stages of the process require different mechanical environments and ECM components...
November 24, 2016: Nature
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