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https://www.readbyqxmd.com/read/29773667/notch-ligand-dll1-mediates-cross-talk-between-mammary-stem-cells-and-the-macrophageal-niche
#1
Rumela Chakrabarti, Toni Celià-Terrassa, Sushil Kumar, Xiang Hang, Yong Wei, Abrar Choudhury, Julie Hwang, Jia Peng, Briana Nixon, John J Grady, Christina DeCoste, Jie Gao, Johan H van Es, Ming O Li, Iannis Aifantis, Hans Clevers, Yibin Kang
The stem cell niche is a specialized environment that dictates stem cell function during development and homeostasis. Here, we show that Dll1, a Notch pathway ligand, is enriched in mammary gland stem cells (MaSCs) and mediates critical interactions with stromal macrophages in the surrounding niche. Conditional deletion of Dll1 reduced the number of MaSCs and impaired ductal morphogenesis in the mammary gland. Moreover, MaSC-expressed Dll1 activates Notch signaling in stromal macrophages, increasing their expression of Wnt family ligands such as Wnt3, Wnt10A, and Wnt16, thereby initiating a feed back loop that promotes the function of Dll1+ MaSCs...
May 17, 2018: Science
https://www.readbyqxmd.com/read/29765026/hematopoietic-stem-cells-can-differentiate-into-restricted-myeloid-progenitors-before-cell-division-in-mice
#2
Tatyana Grinenko, Anne Eugster, Lars Thielecke, Beáta Ramasz, Anja Krüger, Sevina Dietz, Ingmar Glauche, Alexander Gerbaulet, Malte von Bonin, Onur Basak, Hans Clevers, Triantafyllos Chavakis, Ben Wielockx
Hematopoietic stem cells (HSCs) continuously replenish all blood cell types through a series of differentiation steps and repeated cell divisions that involve the generation of lineage-committed progenitors. However, whether cell division in HSCs precedes differentiation is unclear. To this end, we used an HSC cell-tracing approach and Ki67RFP knock-in mice, in a non-conditioned transplantation model, to assess divisional history, cell cycle progression, and differentiation of adult HSCs. Our results reveal that HSCs are able to differentiate into restricted progenitors, especially common myeloid, megakaryocyte-erythroid and pre-megakaryocyte progenitors, without undergoing cell division and even before entering the S phase of the cell cycle...
May 15, 2018: Nature Communications
https://www.readbyqxmd.com/read/29743570/enterovirus-71-infection-of-human-airway-organoids-reveals-vp1-145-as-a-viral-infectivity-determinant
#3
Sabine M G van der Sanden, Norman Sachs, Sylvie M Koekkoek, Gerrit Koen, Dasja Pajkrt, Hans Clevers, Katja C Wolthers
Human enteroviruses frequently cause severe diseases in children. Human enteroviruses are transmitted via the fecal-oral route and respiratory droplets, and primary replication occurs in the gastro-intestinal and respiratory tracts; however, how enteroviruses infect these sites is largely unknown. Human intestinal organoids have recently proven to be valuable tools for studying enterovirus-host interactions in the intestinal tract. In this study, we demonstrated the susceptibility of a newly developed human airway organoid model for enterovirus 71 (EV71) infection...
May 9, 2018: Emerging Microbes & Infections
https://www.readbyqxmd.com/read/29742387/expanding-impact-of-stem-cell-science
#4
EDITORIAL
Hans Clevers
No abstract text is available yet for this article.
May 8, 2018: Stem Cell Reports
https://www.readbyqxmd.com/read/29735715/znrf3-functions-in-mammalian-sex-determination-by-inhibiting-canonical-wnt-signaling
#5
Abigail Harris, Pam Siggers, Silvia Corrochano, Nick Warr, Danielle Sagar, Daniel T Grimes, Makoto Suzuki, Rebecca D Burdine, Feng Cong, Bon-Kyoung Koo, Hans Clevers, Isabelle Stévant, Serge Nef, Sara Wells, Raja Brauner, Bochra Ben Rhouma, Neïla Belguith, Caroline Eozenou, Joelle Bignon-Topalovic, Anu Bashamboo, Ken McElreavey, Andy Greenfield
Mammalian sex determination is controlled by the antagonistic interactions of two genetic pathways: The SRY-SOX9-FGF9 network promotes testis determination partly by opposing proovarian pathways, while RSPO1/WNT-β-catenin/FOXL2 signals control ovary development by inhibiting SRY-SOX9-FGF9. The molecular basis of this mutual antagonism is unclear. Here we show that ZNRF3, a WNT signaling antagonist and direct target of RSPO1-mediated inhibition, is required for sex determination in mice. XY mice lacking ZNRF3 exhibit complete or partial gonadal sex reversal, or related defects...
May 7, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29692415/organoids-in-cancer-research
#6
REVIEW
Jarno Drost, Hans Clevers
The recent advances in in vitro 3D culture technologies, such as organoids, have opened new avenues for the development of novel, more physiological human cancer models. Such preclinical models are essential for more efficient translation of basic cancer research into novel treatment regimens for patients with cancer. Wild-type organoids can be grown from embryonic and adult stem cells and display self-organizing capacities, phenocopying essential aspects of the organs they are derived from. Genetic modification of organoids allows disease modelling in a setting that approaches the physiological environment...
April 24, 2018: Nature Reviews. Cancer
https://www.readbyqxmd.com/read/29643510/intra-tumour-diversification-in-colorectal-cancer-at-the-single-cell-level
#7
Sophie F Roerink, Nobuo Sasaki, Henry Lee-Six, Matthew D Young, Ludmil B Alexandrov, Sam Behjati, Thomas J Mitchell, Sebastian Grossmann, Howard Lightfoot, David A Egan, Apollo Pronk, Niels Smakman, Joost van Gorp, Elizabeth Anderson, Stephen J Gamble, Chris Alder, Marc van de Wetering, Peter J Campbell, Michael R Stratton, Hans Clevers
Every cancer originates from a single cell. During expansion of the neoplastic cell population, individual cells acquire genetic and phenotypic differences from each other. Here, to investigate the nature and extent of intra-tumour diversification, we characterized organoids derived from multiple single cells from three colorectal cancers as well as from adjacent normal intestinal crypts. Colorectal cancer cells showed extensive mutational diversification and carried several times more somatic mutations than normal colorectal cells...
April 11, 2018: Nature
https://www.readbyqxmd.com/read/29593296/automated-brightfield-morphometry-of-3d-organoid-populations-by-organoseg
#8
Michael A Borten, Sameer S Bajikar, Nobuo Sasaki, Hans Clevers, Kevin A Janes
Spheroid and organoid cultures are powerful in vitro models for biology, but size and shape diversity within the culture is largely ignored. To streamline morphometric profiling, we developed OrganoSeg, an open-source software that integrates segmentation, filtering, and analysis for archived brightfield images of 3D culture. OrganoSeg is more accurate and flexible than existing platforms, and we illustrate its potential by stratifying 5167 breast-cancer spheroid and 5743 colon and colorectal-cancer organoid morphologies...
March 28, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29539434/expansion-of-adult-human-pancreatic-tissue-yields-organoids-harboring-progenitor-cells-with-endocrine-differentiation-potential
#9
Cindy J M Loomans, Nerys Williams Giuliani, Jeetindra Balak, Femke Ringnalda, Léon van Gurp, Meritxell Huch, Sylvia F Boj, Toshiro Sato, Lennart Kester, Susana M Chuva de Sousa Lopes, Matthias S Roost, Susan Bonner-Weir, Marten A Engelse, Ton J Rabelink, Harry Heimberg, Robert G J Vries, Alexander van Oudenaarden, Françoise Carlotti, Hans Clevers, Eelco J P de Koning
Generating an unlimited source of human insulin-producing cells is a prerequisite to advance β cell replacement therapy for diabetes. Here, we describe a 3D culture system that supports the expansion of adult human pancreatic tissue and the generation of a cell subpopulation with progenitor characteristics. These cells display high aldehyde dehydrogenase activity (ALDHhi ), express pancreatic progenitors markers (PDX1, PTF1A, CPA1, and MYC), and can form new organoids in contrast to ALDHlo cells. Interestingly, gene expression profiling revealed that ALDHhi cells are closer to human fetal pancreatic tissue compared with adult pancreatic tissue...
March 13, 2018: Stem Cell Reports
https://www.readbyqxmd.com/read/29510215/factor-analysis-defines-distinct-upper-and-lower-gastrointestinal-symptom-groups-compatible-with-rome-iv-criteria-in-a-population-based-study
#10
Egbert Clevers, William E Whitehead, Olafur S Palsson, Ami D Sperber, Hans Törnblom, Lukas Van Oudenhove, Jan Tack, Magnus Simrén
BACKGROUND & AIMS: The Rome IV criteria define functional gastrointestinal (GI) disorders by specific combinations of symptoms. It is possible to empirically evaluate these symptom combinations by factor analysis (a statistical procedure that groups variables that correlate). However, this analysis has not been performed for the Rome IV criteria, and factor analyses based on the previous versions of the Rome criteria did not use population-based data. We therefore investigated symptom grouping by the Rome IV questionnaire using factor analysis of a population-based sample...
March 3, 2018: Clinical Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/29510214/development-of-irritable-bowel-syndrome-features-over-a-5-year-period
#11
Egbert Clevers, Jan Tack, Hans Törnblom, Gisela Ringström, Koen Luyckx, Magnus Simrén, Lukas Van Oudenhove
BACKGROUND & AIMS: There are few data from longitudinal studies of the gastrointestinal and psychologic features of irritable bowel syndrome (IBS). We studied within-person correlations among features of IBS, along with progression of gastrointestinal (GI) symptoms and quality of life, and factors associated with changes over time. METHODS: We performed a longitudinal study of 276 patients with IBS in Sweden (70% female; ages, 19-76 years) who completed questionnaires, each year for 5 years, about their GI symptom severity, quality of life, GI-specific anxiety, general anxiety, depression, and coping resources...
March 3, 2018: Clinical Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/29494240/defining-adult-stem-cells-by-function-not-by-phenotype
#12
Hans Clevers, Fiona M Watt
Central to the classical hematopoietic stem cell (HSC) paradigm is the concept that the maintenance of blood cell numbers is exclusively executed by a discrete physical entity: the transplantable HSC. The HSC paradigm has served as a stereotypic template in stem cell biology, yet the search for rare, hardwired professional stem cells has remained futile in most other tissues. In a more open approach, the focus on the search for stem cells as a physical entity may need to be replaced by the search for stem cell function, operationally defined as the ability of an organ to replace lost cells...
March 1, 2018: Annual Review of Biochemistry
https://www.readbyqxmd.com/read/29311336/troy-brain-stem-cells-cycle-through-quiescence-and-regulate-their-number-by-sensing-niche-occupancy
#13
Onur Basak, Teresa G Krieger, Mauro J Muraro, Kay Wiebrands, Daniel E Stange, Javier Frias-Aldeguer, Nicolas C Rivron, Marc van de Wetering, Johan H van Es, Alexander van Oudenaarden, Benjamin D Simons, Hans Clevers
The adult mouse subependymal zone provides a niche for mammalian neural stem cells (NSCs). However, the molecular signature, self-renewal potential, and fate behavior of NSCs remain poorly defined. Here we propose a model in which the fate of active NSCs is coupled to the total number of neighboring NSCs in a shared niche. Using knock-in reporter alleles and single-cell RNA sequencing, we show that the Wnt target Tnfrsf19/ Troy identifies both active and quiescent NSCs. Quantitative analysis of genetic lineage tracing of individual NSCs under homeostasis or in response to injury reveals rapid expansion of stem-cell number before some return to quiescence...
January 23, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29305587/consensus-molecular-subtypes-of-colorectal-cancer-are-recapitulated-in-in-vitro-and-in-vivo-models
#14
Janneke F Linnekamp, Sander R van Hooff, Pramudita R Prasetyanti, Raju Kandimalla, Joyce Y Buikhuisen, Evelyn Fessler, Prashanthi Ramesh, Kelly A S T Lee, Grehor G W Bochove, Johan H de Jong, Kate Cameron, Ronald van Leersum, Hans M Rodermond, Marek Franitza, Peter Nürnberg, Laura R Mangiapane, Xin Wang, Hans Clevers, Louis Vermeulen, Giorgio Stassi, Jan Paul Medema
Colorectal cancer (CRC) is a highly heterogeneous disease both from a molecular and clinical perspective. Several distinct molecular entities, such as microsatellite instability (MSI), have been defined that make up biologically distinct subgroups with their own clinical course. Recent data indicated that CRC can be best segregated into four groups called consensus molecular subtypes (CMS1-4), each of which has a unique biology and gene expression pattern. In order to develop improved, subtype-specific therapies and to gain insight into the molecular wiring and origin of these subtypes, reliable models are needed...
March 2018: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29298292/imaging-organoids-a-bright-future-ahead
#15
Anne C Rios, Hans Clevers
Organogenesis, tissue homeostasis and organ function involve complex spatial cellular organization and tissue dynamics. The underlying mechanisms of these processes, and how they are disrupted in disease, are challenging to address in vivo and ethically impossible to study in human. Organoids, three-dimensional (3D) stem cell cultures that self-organize into ex vivo 'mini-organs', now open a new window onto cellular processes within tissue. Light microscopy is a powerful approach to probe the cellular complexity that can be modeled with organoids...
January 3, 2018: Nature Methods
https://www.readbyqxmd.com/read/29241552/a-single-cell-rna-sequencing-study-reveals-cellular-and-molecular-dynamics-of-the-hippocampal-neurogenic-niche
#16
Benedetta Artegiani, Anna Lyubimova, Mauro Muraro, Johan H van Es, Alexander van Oudenaarden, Hans Clevers
Adult neurogenesis in the murine dentate gyrus occurs in a specialized microenvironment that sustains the generation of neurons during life. To fully understand adult neurogenesis, it is essential to determine the neural stem cell (NSC) and progenitor developmental stages, their molecular determinants, and the niche cellular and molecular composition. We report on a single-cell RNA sequencing study of the hippocampal niche, performed by isolating all the non-neuronal cell populations. Our analysis provides a comprehensive description of the dentate gyrus cells, and it allows the identification of exclusive cell-type-specific markers...
December 12, 2017: Cell Reports
https://www.readbyqxmd.com/read/29237753/troy-tnfrsf19-marks-epithelial-progenitor-cells-during-mouse-kidney-development-that-continue-to-contribute-to-turnover-in-adult-kidney
#17
Frans Schutgens, Maarten B Rookmaaker, Francis Blokzijl, Ruben van Boxtel, Robert Vries, Edwin Cuppen, Marianne C Verhaar, Hans Clevers
During kidney development, progressively committed progenitor cells give rise to the distinct segments of the nephron, the functional unit of the kidney. Similar segment-committed progenitor cells are thought to be involved in the homeostasis of adult kidney. However, markers for most segment-committed progenitor cells remain to be identified. Here, we evaluate Troy/TNFRSF19 as a segment-committed nephron progenitor cell marker. Troy is expressed in the ureteric bud during embryonic development. During postnatal nephrogenesis, Troy+ cells are present in the cortex and papilla and display an immature tubular phenotype...
December 26, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29224780/a-living-biobank-of-breast-cancer-organoids-captures-disease-heterogeneity
#18
Norman Sachs, Joep de Ligt, Oded Kopper, Ewa Gogola, Gergana Bounova, Fleur Weeber, Anjali Vanita Balgobind, Karin Wind, Ana Gracanin, Harry Begthel, Jeroen Korving, Ruben van Boxtel, Alexandra Alves Duarte, Daphne Lelieveld, Arne van Hoeck, Robert Frans Ernst, Francis Blokzijl, Isaac Johannes Nijman, Marlous Hoogstraat, Marieke van de Ven, David Anthony Egan, Vittoria Zinzalla, Jurgen Moll, Sylvia Fernandez Boj, Emile Eugene Voest, Lodewyk Wessels, Paul Joannes van Diest, Sven Rottenberg, Robert Gerhardus Jacob Vries, Edwin Cuppen, Hans Clevers
Breast cancer (BC) comprises multiple distinct subtypes that differ genetically, pathologically, and clinically. Here, we describe a robust protocol for long-term culturing of human mammary epithelial organoids. Using this protocol, >100 primary and metastatic BC organoid lines were generated, broadly recapitulating the diversity of the disease. BC organoid morphologies typically matched the histopathology, hormone receptor status, and HER2 status of the original tumor. DNA copy number variations as well as sequence changes were consistent within tumor-organoid pairs and largely retained even after extended passaging...
January 11, 2018: Cell
https://www.readbyqxmd.com/read/29215633/measuring-mutation-accumulation-in-single-human-adult-stem-cells-by-whole-genome-sequencing-of-organoid-cultures
#19
Myrthe Jager, Francis Blokzijl, Valentina Sasselli, Sander Boymans, Roel Janssen, Nicolle Besselink, Hans Clevers, Ruben van Boxtel, Edwin Cuppen
Characterization of mutational processes in adult stem cells (ASCs) will improve our understanding of aging-related diseases, such as cancer and organ failure, and may ultimately help prevent the development of these diseases. Here, we present a method for cataloging mutations in individual human ASCs without the necessity of using error-prone whole-genome amplification. Single ASCs are expanded in vitro into clonal organoid cultures to generate sufficient DNA for accurate whole-genome sequencing (WGS) analysis...
January 2018: Nature Protocols
https://www.readbyqxmd.com/read/29212806/syndecan-1-promotes-wnt-%C3%AE-catenin-signaling-in-multiple-myeloma-by-presenting-wnts-and-r-spondins
#20
Zemin Ren, Harmen van Andel, Wim de Lau, Robin B Hartholt, Madelon M Maurice, Hans Clevers, Marie José Kersten, Marcel Spaargaren, Steven T Pals
Multiple myeloma (MM) is characterized by the expansion of malignant plasma cells in the bone marrow (BM). Most MMs display aberrant Wnt/β-catenin signaling, which drives proliferation; however, they lack oncogenic Wnt pathway mutations, suggesting activation by autocrine Wnt ligands and/or paracrine Wnts from the BM microenvironment. Expression of the heparan sulfate (HS) proteoglycan syndecan-1 is a hallmark of MM. Syndecan-1 is a critical player in the complex reciprocal interaction between MM cells and their BM niche, mediating growth factor/cytokine binding and signaling by its HS chains...
March 1, 2018: Blood
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