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205 results on '"Clevers, H.C."'

1. ISSCR Presidents look back on their presidency, the evolution of the field, and the Society

Author

Zon, L., Keller, G., Daley, G.Q., Watt, F.M., Weissman, I.L., Fuchs, E., Gage, F.H., Yamanaka, S., Rossant, J., Morrison, S., Temple, S., Clevers, H.C., Srivastava, D., Mummery, C.L., and Little, M.

Abstract

In celebration of the ISSCR's 20th anniversary we asked past ISSCR presidents the question, "During your presidential year, what key achievements or issue(s) in the field stood out to you?'' The collection of responses provides a glimpse of the evolution of the field and the ISSCR over the past 20 years.

Published
2022

2. An organoid-derived bronchioalveolar model for SARS-CoV-2 infection of human alveolar type II-like cells

Author

Lamers, M.M. (Mart M.), van der Vaart, J. (Jelte), Knoops, K. (Kèvin), Riesebosch, S. (Samra), Breugem, T.I. (Tim I), Mykytyn, A.Z. (Anna Z), Beumer, J. (Joep), Schipper, D. (Debby), Bezstarosti, K. (Karel), Koopman, C.D. (Charlotte D), Groen, N. (Nathalie), Ravelli, R.B.G. (Raimond B.), Duimel, H.Q. (Hans Q), Demmers, J.A.A. (Jeroen), Verjans, G.M.G.M. (George), Koopmans D.V.M., M.P.G. (Marion), Muraro, M.J. (Mauro J), Peters, P.J. (Peter J), Clevers, H.C. (Hans), Haagmans, B.L. (Bart), Lamers, M.M. (Mart M.), van der Vaart, J. (Jelte), Knoops, K. (Kèvin), Riesebosch, S. (Samra), Breugem, T.I. (Tim I), Mykytyn, A.Z. (Anna Z), Beumer, J. (Joep), Schipper, D. (Debby), Bezstarosti, K. (Karel), Koopman, C.D. (Charlotte D), Groen, N. (Nathalie), Ravelli, R.B.G. (Raimond B.), Duimel, H.Q. (Hans Q), Demmers, J.A.A. (Jeroen), Verjans, G.M.G.M. (George), Koopmans D.V.M., M.P.G. (Marion), Muraro, M.J. (Mauro J), Peters, P.J. (Peter J), Clevers, H.C. (Hans), and Haagmans, B.L. (Bart)

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which may result in acute respiratory distress syndrome (ARDS), multiorga

Published
2021
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3. Human extrahepatic and intrahepatic cholangiocyte organoids show region-specific differentiation potential and model cystic fibrosis-related bile duct disease

Author

Verstegen, M.M.A. (Monique), Roos, F.J.M. (Floris J M), Burka, K. (Ksenia), Gehart, H. (Helmuth), Jager, M. (Myrthe), de Wolf, M. (Maaike), Bijvelds, M.J.C. (Marcel), Jonge, H.R. (Hugo) de, Ardisasmita, A.I. (Arif I.), Huizen, N.A. (Nick) van, Roest, H.P. (Henk), Jonge, J. (Jeroen) de, Koch, M. (Michael), Pampaloni, F. (Francesco), Fuchs, S.A. (Sabine A.), Schene, I.F. (Imre F.), Luider, T.M. (Theo), Doef, H.P. (Hubert) van der, Bodewes, F.A.J.A. (Frank), Kleine, R.H.J. (Ruben) de, Spee, B. (B.), Kremers, G.J. (Gert-Jan), Clevers, H.C. (Hans), IJzermans, J.N.M. (Jan), Cuppen, E. (Edwin), Laan, L.J.W. (Luc) van der, Verstegen, M.M.A. (Monique), Roos, F.J.M. (Floris J M), Burka, K. (Ksenia), Gehart, H. (Helmuth), Jager, M. (Myrthe), de Wolf, M. (Maaike), Bijvelds, M.J.C. (Marcel), Jonge, H.R. (Hugo) de, Ardisasmita, A.I. (Arif I.), Huizen, N.A. (Nick) van, Roest, H.P. (Henk), Jonge, J. (Jeroen) de, Koch, M. (Michael), Pampaloni, F. (Francesco), Fuchs, S.A. (Sabine A.), Schene, I.F. (Imre F.), Luider, T.M. (Theo), Doef, H.P. (Hubert) van der, Bodewes, F.A.J.A. (Frank), Kleine, R.H.J. (Ruben) de, Spee, B. (B.), Kremers, G.J. (Gert-Jan), Clevers, H.C. (Hans), IJzermans, J.N.M. (Jan), Cuppen, E. (Edwin), and Laan, L.J.W. (Luc) van der

Abstract

The development, homeostasis, and repair of intrahepatic and extrahepatic bile ducts are thought to involve distinct mechanisms including proliferation and maturation of cholangiocyte and progenitor cells. This study aimed to characterize human extrahepatic cholangiocyte organoids (ECO) using canonical Wnt-stimulated culture medium previously developed for intrahepatic cholangiocyte organoids (ICO). Paired ECO and ICO were derived from common bile duct and liver tissue, respectively. Characterization showed both organoid types were highly similar, though some differences in size and gene expression were observed. Both ECO and ICO have cholangiocyte fate differentiation capacity. However, unlike ICO, ECO lack the potential for differentiation towards a hepatocyte-like fate. Importantly, ECO derived from a cystic fibrosis patient showed no

Published
2020
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4. LifeTime and improving European healthcare through cell-based interceptive medicine

Author

Rajewsky, N. (Nikolaus), Almouzni, G. (Geneviève), Gorski, S.A. (Stanislaw A.), Aerts, S. (Stein), Amit, I. (Ido), Bertero, M.G. (Michela G.), Bock, C. (Christoph), Bredenoord, A.L. (Annelien L.), Cavalli, G. (Giacomo), Chiocca, S. (Susanna), Clevers, H.C. (Hans), Strooper, B. (Bart) de, Eggert, A. (Angelika), Ellenberg, J. (Jan), Fernández, X.M. (Xosé M.), Figlerowicz, M. (Marek), Gasser, S.M. (Susan M.), Hübner, N. (Norbert), Kjems, J. (Jørgen), Knoblich, J.A. (Jürgen A.), Krabbe, G. (Grietje), Lichter, P. (Peter), Linnarsson, S. (Sten), Marine, J.-C. (J.), Marioni, J. (John), Marti-Renom, M.A. (Marc A.), Netea, M.G. (Mihai), Nickel, D. (Dörthe), Nollmann, M. (Marcelo), Novak, H.R. (Halina R.), Parkinson, H. (Helen), Piccolo, S. (Stefano), Pinheiro, I. (Inês), Pombo, A. (Ana), Popp, C. (Christian), Reik, W. (Wolf), Roman-Roman, S. (Sergio), Rosenstiel, P. (Philip), Schultze, J.L. (Joachim), Stegle, O. (Oliver), Tanay, A. (Amos), Testa, G. (Giuseppe), Thanos, D. (Dimitris), Theis, F. (Fabian), Torres-Padilla, M.-E. (Maria-Elena), Valencia, A. (Alfonso), Vallot, C. (Céline), van Oudenaarden, A. (Alexander), Vidal, M. (Marie), Voet, T. (Thierry), Alberi, L. (Lavinia), Alexander, S. (Stephanie), Alexandrov, T. (Theodore), Arenas, E. (Ernest), Bagni, C. (Claudia), Balderas, R. (Robert), Bandelli, A. (Andrea), Becher, B. (Burkhard), Becker, M. (Matthias), Beerenwinkel, N. (Niko), Benkirame, M. (Monsef), Beyer, M. (Marc), Bickmore, W. (Wendy), Biessen, E.E.A.L. (Erik E.A.L.), Blomberg, N. (Niklas), Blumcke, I. (Ingmar), Bodenmiller, B. (Bernd), Borroni, B. (Barbara), Boumpas, D.T. (Dimitrios T.), Bourgeron, T. (Thomas), Bowers, S. (Sarion), Braeken, D. (Dries), Brooksbank, C. (Catherine), Brose, N. (Nils), Bruining, J. (Hans), Bury, J. (Jo), Caporale, N. (Nicolo), Cattoretti, G. (Giorgio), Chabane, N. (Nadia), Chneiweiss, H. (Hervé), Cook, S.A. (Stuart A.), Curatolo, P. (Paolo), Jonge, M.I. (Marien) de, Deplancke, B. (Bart), De Strooper, B. (Bart), de Witte, P. (Peter), Dimmeler, S. (Stefanie), Draganski, B. (Bogdan), Drews, A.-D. (Anna-Dorothee), Dumbrava, C. (Costica), Engelhardt, S. (Stefan), Gasser, T. (Thomas), Giamarellos-Bourboulis, E. (Evangelos), Graff, C. (Caroline), Grün, D. (Dominic), Gut, I. (Ivo), Hansson, O. (Oskar), Henshall, D.C. (David C.), Herland, A. (Anna), Heutink, P. (Peter), Heymans, S. (Stephane), Heyn, H. (Holger), Huch, M. (Meritxell), Huitinga, I. (Inge), Jackowiak, P. (Paulina), Jongsma, K.R. (Karin), Journot, L. (Laurent), Junker, J.P. (Jan Philipp), Katz, S. (Shauna), Kehren, J. (Jeanne), Kempa, S. (Stefan), Kirchhof, P. (Paulus), Klein, C. (Christoph), Koralewska, N. (Natalia), Korbel, J.O. (Jan), Kühnemund, M. (Malte), Lamond, A.I. (Angus I.), Lauwers, E. (Elsa), Le Ber, I. (Isabelle), Leinonen, V. (Ville), Tobon, A.L. (Alejandro Lopez), Lundberg, E. (Emma), Lunkes, A. (Astrid), Maatz, H. (Henrike), Mann, M. (Mathias), Marelli, L. (Luca), Matser, V. (Vera), Matthews, P.M. (P.), Mechta-Grigoriou, F. (Fatima), Menon, R. (Radhika), Nielsen, A.F. (Anne F.), Pagani, M. (Massimiliano), Pasterkamp, R.J. (Jeroen), Pitkanen, A. (Asla), Popescu, V. (Valentin), Pottier, C. (Cyril), Puisieux, A. (Alain), Rademakers, R. (Rosa), Reiling, D. (Dory), Reiner, O. (Orly), Remondini, D. (Daniel), Ritchie, C. (Craig), Rohrer, J.D. (Jonathan D.), Saliba, A.-E. (Antione-Emmanuel), Sánchez-Valle, R. (Raquel), Santosuosso, A. (Amedeo), Sauter, A. (Arnold), Scheltema, R.A. (Richard A.), Scheltens, P. (Philip), Schiller, H.B. (Herbert B.), Schneider, A. (Anja), Seibler, P. (Philip), Sheehan-Rooney, K. (Kelly), Shields, D. (David), Sleegers, K. (Kristel), Smit, G. (Guus), Smith, K.G.C. (Kenneth G. C.), Smolders, I. (Ilse), Synofzik, M. (Matthis), Tam, W.L. (Wai Long), Teichmann, S. (Sarah), Thom, M. (Maria), Turco, M.Y. (Margherita Y.), Beusekom, H.M.M. (Heleen) van, Vandenberghe, R. (Rik), den Hoecke, S.V. (Silvie Van), Van de Poel, E. (Ellen), der Ven, A. (Andre van), van der Zee, J. (Julie), van Lunzen, J. (Jan), van Minnebruggen, G. (Geert), Van Paesschen, W. (Wim), Swieten, J.C. (John) van, van Vught, R. (Remko), Verhage, M. (Matthijs), Verstreken, P. (Patrik), Villa, C.E. (Carlo Emanuele), Vogel, J. (Jörg), Kalle, C. (Christof) von, Walter, J. (Jörn), Weckhuysen, S. (Sarah), Weichert, W. (Wilko), Wood, L. (Louisa), Ziegler, A.-G. (Anette-Gabriele), Zipp, F. (Frauke), Rajewsky, N. (Nikolaus), Almouzni, G. (Geneviève), Gorski, S.A. (Stanislaw A.), Aerts, S. (Stein), Amit, I. (Ido), Bertero, M.G. (Michela G.), Bock, C. (Christoph), Bredenoord, A.L. (Annelien L.), Cavalli, G. (Giacomo), Chiocca, S. (Susanna), Clevers, H.C. (Hans), Strooper, B. (Bart) de, Eggert, A. (Angelika), Ellenberg, J. (Jan), Fernández, X.M. (Xosé M.), Figlerowicz, M. (Marek), Gasser, S.M. (Susan M.), Hübner, N. (Norbert), Kjems, J. (Jørgen), Knoblich, J.A. (Jürgen A.), Krabbe, G. (Grietje), Lichter, P. (Peter), Linnarsson, S. (Sten), Marine, J.-C. (J.), Marioni, J. (John), Marti-Renom, M.A. (Marc A.), Netea, M.G. (Mihai), Nickel, D. (Dörthe), Nollmann, M. (Marcelo), Novak, H.R. (Halina R.), Parkinson, H. (Helen), Piccolo, S. (Stefano), Pinheiro, I. (Inês), Pombo, A. (Ana), Popp, C. (Christian), Reik, W. (Wolf), Roman-Roman, S. (Sergio), Rosenstiel, P. (Philip), Schultze, J.L. (Joachim), Stegle, O. (Oliver), Tanay, A. (Amos), Testa, G. (Giuseppe), Thanos, D. (Dimitris), Theis, F. (Fabian), Torres-Padilla, M.-E. (Maria-Elena), Valencia, A. (Alfonso), Vallot, C. (Céline), van Oudenaarden, A. (Alexander), Vidal, M. (Marie), Voet, T. (Thierry), Alberi, L. (Lavinia), Alexander, S. (Stephanie), Alexandrov, T. (Theodore), Arenas, E. (Ernest), Bagni, C. (Claudia), Balderas, R. (Robert), Bandelli, A. (Andrea), Becher, B. (Burkhard), Becker, M. (Matthias), Beerenwinkel, N. (Niko), Benkirame, M. (Monsef), Beyer, M. (Marc), Bickmore, W. (Wendy), Biessen, E.E.A.L. (Erik E.A.L.), Blomberg, N. (Niklas), Blumcke, I. (Ingmar), Bodenmiller, B. (Bernd), Borroni, B. (Barbara), Boumpas, D.T. (Dimitrios T.), Bourgeron, T. (Thomas), Bowers, S. (Sarion), Braeken, D. (Dries), Brooksbank, C. (Catherine), Brose, N. (Nils), Bruining, J. (Hans), Bury, J. (Jo), Caporale, N. (Nicolo), Cattoretti, G. (Giorgio), Chabane, N. (Nadia), Chneiweiss, H. (Hervé), Cook, S.A. (Stuart A.), Curatolo, P. (Paolo), Jonge, M.I. (Marien) de, Deplancke, B. (Bart), De Strooper, B. (Bart), de Witte, P. (Peter), Dimmeler, S. (Stefanie), Draganski, B. (Bogdan), Drews, A.-D. (Anna-Dorothee), Dumbrava, C. (Costica), Engelhardt, S. (Stefan), Gasser, T. (Thomas), Giamarellos-Bourboulis, E. (Evangelos), Graff, C. (Caroline), Grün, D. (Dominic), Gut, I. (Ivo), Hansson, O. (Oskar), Henshall, D.C. (David C.), Herland, A. (Anna), Heutink, P. (Peter), Heymans, S. (Stephane), Heyn, H. (Holger), Huch, M. (Meritxell), Huitinga, I. (Inge), Jackowiak, P. (Paulina), Jongsma, K.R. (Karin), Journot, L. (Laurent), Junker, J.P. (Jan Philipp), Katz, S. (Shauna), Kehren, J. (Jeanne), Kempa, S. (Stefan), Kirchhof, P. (Paulus), Klein, C. (Christoph), Koralewska, N. (Natalia), Korbel, J.O. (Jan), Kühnemund, M. (Malte), Lamond, A.I. (Angus I.), Lauwers, E. (Elsa), Le Ber, I. (Isabelle), Leinonen, V. (Ville), Tobon, A.L. (Alejandro Lopez), Lundberg, E. (Emma), Lunkes, A. (Astrid), Maatz, H. (Henrike), Mann, M. (Mathias), Marelli, L. (Luca), Matser, V. (Vera), Matthews, P.M. (P.), Mechta-Grigoriou, F. (Fatima), Menon, R. (Radhika), Nielsen, A.F. (Anne F.), Pagani, M. (Massimiliano), Pasterkamp, R.J. (Jeroen), Pitkanen, A. (Asla), Popescu, V. (Valentin), Pottier, C. (Cyril), Puisieux, A. (Alain), Rademakers, R. (Rosa), Reiling, D. (Dory), Reiner, O. (Orly), Remondini, D. (Daniel), Ritchie, C. (Craig), Rohrer, J.D. (Jonathan D.), Saliba, A.-E. (Antione-Emmanuel), Sánchez-Valle, R. (Raquel), Santosuosso, A. (Amedeo), Sauter, A. (Arnold), Scheltema, R.A. (Richard A.), Scheltens, P. (Philip), Schiller, H.B. (Herbert B.), Schneider, A. (Anja), Seibler, P. (Philip), Sheehan-Rooney, K. (Kelly), Shields, D. (David), Sleegers, K. (Kristel), Smit, G. (Guus), Smith, K.G.C. (Kenneth G. C.), Smolders, I. (Ilse), Synofzik, M. (Matthis), Tam, W.L. (Wai Long), Teichmann, S. (Sarah), Thom, M. (Maria), Turco, M.Y. (Margherita Y.), Beusekom, H.M.M. (Heleen) van, Vandenberghe, R. (Rik), den Hoecke, S.V. (Silvie Van), Van de Poel, E. (Ellen), der Ven, A. (Andre van), van der Zee, J. (Julie), van Lunzen, J. (Jan), van Minnebruggen, G. (Geert), Van Paesschen, W. (Wim), Swieten, J.C. (John) van, van Vught, R. (Remko), Verhage, M. (Matthijs), Verstreken, P. (Patrik), Villa, C.E. (Carlo Emanuele), Vogel, J. (Jörg), Kalle, C. (Christof) von, Walter, J. (Jörn), Weckhuysen, S. (Sarah), Weichert, W. (Wilko), Wood, L. (Louisa), Ziegler, A.-G. (Anette-Gabriele), and Zipp, F. (Frauke)

Abstract

LifeTime aims to track, understand and target human cells during the onset and progression of complex diseases and their response to therapy at single-cell resolution. This mission will be implemented through the development and integration of single-cell multi-omics and imaging, artificial intelligence and patient-derived experimental disease models during progression from health to disease. Analysis of such large molecular and clinical datasets will discover molecular mechanisms, create predictive computational models of disease progression, and reveal new drug targets and therapies. Timely detection and interception of disease embedded in an ethical and patient-centered vision will be achieved through interactions across academia, hospitals, patient-associations, health data management systems and industry. Applying this strategy to key medical challenges in cancer, neurological, infectious, chronic inflammatory and cardiovascular diseases at the single-cell level will usher in cell-based interceptive medicine in Europe over the next decade.

Published
2020
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5. SARS-CoV-2 productively infects human gut enterocytes

Author

Lamers, M.M. (Mart M.), Beumer, J. (Joep), van der Vaart, J. (Jelte), Knoops, K. (Kèvin), Puschhof, J. (Jens), Breugem, T.I. (Tim I.), Ravelli, R.B.G. (Raimond B.), Paul van Schayck, J. (J.), Mykytyn, A.Z. (Anna Z.), Duimel, H.Q. (Hans Q.), van Donselaar, E. (Elly), Riesebosch, S. (Samra), Kuijpers, H.J.H. (Helma J H), Schipper, D. (Debby), van de Wetering, W.J. (Willine J.), Graaf, M. (Miranda) de, Koopmans D.V.M., M.P.G. (Marion), Cuppen, E. (Edwin), Peters, P.J. (Peter J.), Haagmans, B.L. (Bart), Clevers, H.C. (Hans), Lamers, M.M. (Mart M.), Beumer, J. (Joep), van der Vaart, J. (Jelte), Knoops, K. (Kèvin), Puschhof, J. (Jens), Breugem, T.I. (Tim I.), Ravelli, R.B.G. (Raimond B.), Paul van Schayck, J. (J.), Mykytyn, A.Z. (Anna Z.), Duimel, H.Q. (Hans Q.), van Donselaar, E. (Elly), Riesebosch, S. (Samra), Kuijpers, H.J.H. (Helma J H), Schipper, D. (Debby), van de Wetering, W.J. (Willine J.), Graaf, M. (Miranda) de, Koopmans D.V.M., M.P.G. (Marion), Cuppen, E. (Edwin), Peters, P.J. (Peter J.), Haagmans, B.L. (Bart), and Clevers, H.C. (Hans)

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause coronavirus disease 2019 (COVID-19), an influenza-like disease that is primarily thought to infect the lungs with transmission through the respiratory route. However, clinical evidence suggests that the intestine may present another viral target organ. Indeed, the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) is highly expressed on differentiated enterocytes. In human small intestinal organoids (hSIOs), enterocytes were readily infected by SARS-CoV and SARS-CoV-2, as demonstrated by confocal and electron microscopy. Enterocytes produced infectious viral particles, whereas messenger RNA expression analysis of hSIOs revealed induction of a generic viral response program. Therefore, the intestinal epithelium supports SARS-CoV-2 replication, and hSIOs serve as an experimental model for coronavirus infection and biology.

Published
2020
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6. Patient-derived oral mucosa organoids as an in vitro model for methotrexate induced toxicity in pediatric acute lymphoblastic leukemia

Author

Driehuis, E. (E.), Oosterom, N. (Natanja), Heil, S.G. (Sandra), Muller, I.B. (I. B.), Lin, M. (M.), Kolders, S. (S.), Jansen, G. (Gert), Jonge, R. (Robert) de, Pieters, R. (Rob), Clevers, H.C. (Hans), Heuvel-Eibrink, M.M. (Marry) van den, Driehuis, E. (E.), Oosterom, N. (Natanja), Heil, S.G. (Sandra), Muller, I.B. (I. B.), Lin, M. (M.), Kolders, S. (S.), Jansen, G. (Gert), Jonge, R. (Robert) de, Pieters, R. (Rob), Clevers, H.C. (Hans), and Heuvel-Eibrink, M.M. (Marry) van den

Abstract

We have recently established a protocol to grow wildtype human oral mucosa organoids. These three-dimensional structures can be maintained in culture long-term, do not require immortalization, and recapitulate the multilayered composition of the epithelial lining of the oral mucosa. Here, we validate the use of this model to study the effect of Leucovorin (LV) on Methotrexate (MTX)-induced toxicity. MTX is a chemotherapeutic agent used in the treatment of pediatric acute lymphoblastic leukemia. Although effective, the use of MTX often results in se

Published
2020
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7. Cysteamine-bicalutamide combination treatment restores alpha-ketoglutarate and corrects proximal tubule phenotype in cystinosis

Author

Afd Pharmacology, Afd Biomol.Mass Spect. and Proteomics, Dep Scheikunde, Veterinaire biochemie, dB&C FR-RMSC RMSC, Sub Biomol.Mass Spectrometry & Proteom., Pharmacology, Biomolecular Mass Spectrometry and Proteomics, Jamalpoor, A., van Gelder, C.A.G.H., Yousef Yengej, Fjodor A., Zaal, E.A., Berlingerio, Sante Princiero, Veys, Koenraad R., Pou Casellas, C., Voskuil, Koen, Essa, Khaled, Ammerlaan, Carola, Rega, Laura Rita, van der Welle, Reini, Lilien, M.R., Rookmaaker, M.B., Clevers, H.C., Klumperman, J., Levtchenko, Elena, Berkers, C.R., Verhaar, Marianne C, Altelaar, A.F.M., Masereeuw, Rosalinde, Janssen, M.J., Afd Pharmacology, Afd Biomol.Mass Spect. and Proteomics, Dep Scheikunde, Veterinaire biochemie, dB&C FR-RMSC RMSC, Sub Biomol.Mass Spectrometry & Proteom., Pharmacology, Biomolecular Mass Spectrometry and Proteomics, Jamalpoor, A., van Gelder, C.A.G.H., Yousef Yengej, Fjodor A., Zaal, E.A., Berlingerio, Sante Princiero, Veys, Koenraad R., Pou Casellas, C., Voskuil, Koen, Essa, Khaled, Ammerlaan, Carola, Rega, Laura Rita, van der Welle, Reini, Lilien, M.R., Rookmaaker, M.B., Clevers, H.C., Klumperman, J., Levtchenko, Elena, Berkers, C.R., Verhaar, Marianne C, Altelaar, A.F.M., Masereeuw, Rosalinde, and Janssen, M.J.

Published
2020

9. Large-Scale Production of LGR5-Positive Bipotential Human Liver Stem Cells

Author

Schneeberger, K. (Kerstin), Sánchez-Romero, N. (Natalia), Ye, S. (Shicheng), Steenbeek, F.G. (Frank) van, Oosterhoff, L.A. (Loes A.), Pla Palacin, I. (Iris), Chen, C. (Chen), Wolferen, M.E. (Monique) van, van Tienderen, G. (Gilles), Lieshout, R. (Ruby), Colemonts-Vroninks, H. (Haaike), Schene, I. (Imre), Hoekstra, R. (Ruurdtje), Verstegen, M.M.A. (Monique), Laan, L.J.W. (Luc) van der, Penning, C. (Corine), Fuchs, S.A. (Sabine A.), Clevers, H.C. (Hans), De Kock, J. (Joery), Baptista, P.M. (Pedro M.), Spee, B. (B.), Schneeberger, K. (Kerstin), Sánchez-Romero, N. (Natalia), Ye, S. (Shicheng), Steenbeek, F.G. (Frank) van, Oosterhoff, L.A. (Loes A.), Pla Palacin, I. (Iris), Chen, C. (Chen), Wolferen, M.E. (Monique) van, van Tienderen, G. (Gilles), Lieshout, R. (Ruby), Colemonts-Vroninks, H. (Haaike), Schene, I. (Imre), Hoekstra, R. (Ruurdtje), Verstegen, M.M.A. (Monique), Laan, L.J.W. (Luc) van der, Penning, C. (Corine), Fuchs, S.A. (Sabine A.), Clevers, H.C. (Hans), De Kock, J. (Joery), Baptista, P.M. (Pedro M.), and Spee, B. (B.)

Abstract

Background and Aims: The gap between patients on transplant waiting lists and available donor organs is steadily increasing. Hu

Published
2019
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10. Rectal Organoids Enable Personalized Treatment of Cystic Fibrosis

Author

Berkers, G, van Mourik, P., Vonk, AM, Kruisselbrink, E, Dekkers, J.F. (Johanna), de Winter-de Groot, KM, Arets, H.G. (Hubertus), Marck-van der Wilt, R.E.P., Dijkema, J.S., Vanderschuren, M.M., Houwen, R.H.J. (Roderick), Heijerman, H.G.M. (Harry), van de Graaf, E.A., Elias, S.G. (Sjoerd), Majoor, CJ, Koppelman, G.H. (Gerard), Roukema, J. (Jolt), de Bakker, M., Janssens, H.M. (Hettie), van der Meer, R., Vries, R.G.J. (Robert), Clevers, H.C. (Hans), Jonge, H.R. (Hugo) de, Beekman, J.M. (Jeffrey), Ent, C.K. (Cornelis) van der, Berkers, G, van Mourik, P., Vonk, AM, Kruisselbrink, E, Dekkers, J.F. (Johanna), de Winter-de Groot, KM, Arets, H.G. (Hubertus), Marck-van der Wilt, R.E.P., Dijkema, J.S., Vanderschuren, M.M., Houwen, R.H.J. (Roderick), Heijerman, H.G.M. (Harry), van de Graaf, E.A., Elias, S.G. (Sjoerd), Majoor, CJ, Koppelman, G.H. (Gerard), Roukema, J. (Jolt), de Bakker, M., Janssens, H.M. (Hettie), van der Meer, R., Vries, R.G.J. (Robert), Clevers, H.C. (Hans), Jonge, H.R. (Hugo) de, Beekman, J.M. (Jeffrey), and Ent, C.K. (Cornelis) van der

Abstract

In vitro drug tests using patient-derived stem cell cultures offer opportunities to individually select efficacious treatments. Here, we provide a study that demonstrates that in vitro drug responses in rectal organoids from individual patients with cystic fibrosis (CF) correlate with changes in two in vivo therapeutic endpoints. We measured individual in vitro efficaciousness using a functional assay in rectum-derived organoids based on forskolininduced swelling and studied the correlation with in vivo effects. The in vitro organoid responses correlated with both change in pulmonary response and change in sweat chloride concentration. Receiver operating characteristic curves indicated good-toexcellent accuracy of the organoid-based test for defining clinical responses. This study indicates that an in vitro assay using stem cell cultures can prospectively select efficacious treatments for patients and suggests that biobanked stem cell resources can be used to tailor individual treatments in a cost-effective and patient-friendly manner.

Published
2019
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11. Structure of Stem Cell Growth Factor R-spondin 1 in Complex with the Ectodomain of Its Receptor LGR5

Author

Peng, W.C., de Lau, W., Forneris, F., Granneman, J.C.M., Clevers, H.C., Gros, P., Crystal and Structural Chemistry, Sub Crystal and Structural Chemistry, Dep Biologie, and Hubrecht Institute for Developmental Biology and Stem Cell Research

Subjects
Models, Molecular, Gene Expression, Biology, Transfection, General Biochemistry, Genetics and Molecular Biology, Receptors, G-Protein-Coupled, 03 medical and health sciences, Structure-Activity Relationship, 0302 clinical medicine, Humans, Receptor, RSPO1, lcsh:QH301-705.5, 030304 developmental biology, 0303 health sciences, HEK 293 cells, Spondin 1, Wnt signaling pathway, LGR5, Cell biology, HEK293 Cells, Ectodomain, Biochemistry, lcsh:Biology (General), 030220 oncology & carcinogenesis, Intercellular Signaling Peptides and Proteins, Signal transduction, Thrombospondins, Signal Transduction
Abstract

SummaryLeucine-rich repeat-containing G protein-coupled receptors 4–6 (LGR4–LGR6) are receptors for R-spondins, potent Wnt agonists that exert profound trophic effects on Wnt-driven stem cells compartments. We present crystal structures of a signaling-competent fragment of R-spondin 1 (Rspo1) at a resolution of 2.0 Å and its complex with the LGR5 ectodomain at a resolution of 3.2 Å. Ecto-LGR5 binds Rspo1 at its concave leucine-rich-repeat (LRR) surface, forming a dimeric 2:2 complex. Fully conserved residues on LGR4–LGR6 explain promiscuous binding of R-spondins. A phenylalanine clamp formed by Rspo1 Phe106 and Phe110 pinches Ala190 of LGR5 and is critical for binding. Mutations related to congenital anonychia reduce signaling, but not binding of Rspo1 to LGR5. Furthermore, antibody binding to the extended loop of the C-terminal LRR cap of LGR5 activates signaling in a ligand-independent manner. Thus, our data reveal binding of R-spondins to conserved sites on LGR4–LGR6 and, in analogy to FSHR and related receptors, suggest a direct signaling role for LGR4–LGR6 in addition to its formation of Wnt receptor and coreceptor complexes.

Published
2013
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12. Long-Term Adult Feline Liver Organoid Cultures for Disease Modeling of Hepatic Steatosis

Author

Kruitwagen, H.S. (Hedwig S.), Oosterhoff, L.A. (Loes A.), Vernooij, I.G.W.H. (Ingrid G.W.H.), Schrall, I.M. (Ingrid M.), Wolferen, M.E. (Monique) van, Bannink, F. (Farah), Roesch, C. (Camille), van Uden, L. (Lisa), Molenaar, M.R. (Martijn R.), Helms, J.B. (J. Bernd), Grinwis, G.C.M. (Guy C.), Verstegen, M.M.A. (Monique), Laan, L.J.W. (Luc) van der, Huch, M. (Meritxell), Geijsen, N. (Niels), Vries, R.G.J. (Robert), Clevers, H.C. (Hans), Rothuizen, J. (J.), Schotanus, B.A. (Baukje A.), Penning, C. (Corine), Spee, B. (B.), Kruitwagen, H.S. (Hedwig S.), Oosterhoff, L.A. (Loes A.), Vernooij, I.G.W.H. (Ingrid G.W.H.), Schrall, I.M. (Ingrid M.), Wolferen, M.E. (Monique) van, Bannink, F. (Farah), Roesch, C. (Camille), van Uden, L. (Lisa), Molenaar, M.R. (Martijn R.), Helms, J.B. (J. Bernd), Grinwis, G.C.M. (Guy C.), Verstegen, M.M.A. (Monique), Laan, L.J.W. (Luc) van der, Huch, M. (Meritxell), Geijsen, N. (Niels), Vries, R.G.J. (Robert), Clevers, H.C. (Hans), Rothuizen, J. (J.), Schotanus, B.A. (Baukje A.), Penning, C. (Corine), and Spee, B. (B.)

Abstract

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. Next, organoids from mouse, human, dog

Published
2017
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13. Peutz-Jeghers syndrome polyps are polyclonal with expanded progenitor cell compartment

Author

de Leng, W.W.J., Jansen, M., Keller, J.J., de Gijsel, M., Milne, A.N.A., Morsink, F.H.M., Weterman, M.A.J., Iacobuzio-Donahue, C.A., Clevers, H.C., Giardiello, F.M., and Offerhaus, G.J.A.

Subjects
Peutz-Jeghers syndrome -- Genetic aspects, Peutz-Jeghers syndrome -- Development and progression, Peutz-Jeghers syndrome -- Risk factors, Health
Published
2007

17. Retromer dependent recycling of the Wnt secretion factor Wls is dispensable for stem cell maintenance in the mammalian intestinal epithelium

Author

de Groot, R.E., Farin, H.F., Macurkova, M., van Es, J.H., Clevers, H.C., Korswagen, H.C., de Groot, R.E., Farin, H.F., Macurkova, M., van Es, J.H., Clevers, H.C., and Korswagen, H.C.

Abstract

In C. elegans and Drosophila, retromer mediated retrograde transport of Wntless (Wls) from endosomes to the trans-Golgi network (TGN) is required for Wnt secretion. When this retrograde transport pathway is blocked, Wls is missorted to lysosomes and degraded, resulting in reduced Wnt secretion and various Wnt related phenotypes. In the mammalian intestine, Wnt signaling is essential to maintain stem cells. This prompted us to ask if retromer mediated Wls recycling is also important for Wnt signaling and stem cell maintenance in this system. To answer this question, we generated a conditional Vps35 (fl) allele. As Vps35 is an essential subunit of the retromer complex, this genetic tool allowed us to inducibly interfere with retromer function in the intestinal epithelium. Using a pan-intestinal epithelial Cre line (Villin-CreERT2), we did not observe defects in crypt or villus morphology after deletion of Vps35 from the intestinal epithelium. Wnt secreted from the mesenchyme of the intestine may compensate for a reduction in epithelial Wnt secretion. To exclude the effect of the mesenchyme, we generated intestinal organoid cultures. Loss of Vps35 in intestinal organoids did not affect the overall morphology of the organoids. We were able to culture Vps35 (/) organoids for many passages without Wnt supplementation in the growth medium. However, Wls protein levels were reduced and we observed a subtle growth defect in the Vps35 (/) organoids. These results confirm the role of retromer in the retrograde trafficking of Wls in the intestine, but show that retromer mediated Wls recycling is not essential to maintain Wnt signaling or stem cell proliferation in the intestinal epithelium., In C. elegans and Drosophila, retromer mediated retrograde transport of Wntless (Wls) from endosomes to the trans-Golgi network (TGN) is required for Wnt secretion. When this retrograde transport pathway is blocked, Wls is missorted to lysosomes and degraded, resulting in reduced Wnt secretion and various Wnt related phenotypes. In the mammalian intestine, Wnt signaling is essential to maintain stem cells. This prompted us to ask if retromer mediated Wls recycling is also important for Wnt signaling and stem cell maintenance in this system. To answer this question, we generated a conditional Vps35 (fl) allele. As Vps35 is an essential subunit of the retromer complex, this genetic tool allowed us to inducibly interfere with retromer function in the intestinal epithelium. Using a pan-intestinal epithelial Cre line (Villin-CreERT2), we did not observe defects in crypt or villus morphology after deletion of Vps35 from the intestinal epithelium. Wnt secreted from the mesenchyme of the intestine may compensate for a reduction in epithelial Wnt secretion. To exclude the effect of the mesenchyme, we generated intestinal organoid cultures. Loss of Vps35 in intestinal organoids did not affect the overall morphology of the organoids. We were able to culture Vps35 (/) organoids for many passages without Wnt supplementation in the growth medium. However, Wls protein levels were reduced and we observed a subtle growth defect in the Vps35 (/) organoids. These results confirm the role of retromer in the retrograde trafficking of Wls in the intestine, but show that retromer mediated Wls recycling is not essential to maintain Wnt signaling or stem cell proliferation in the intestinal epithelium.

Published
2013

18. Paneth cells: maestros of the small intestinal crypts

Author

Clevers, H.C., Bevins, C.L., Clevers, H.C., and Bevins, C.L.

Abstract

Paneth cells are highly specialized epithelial cells of the small intestine, where they coordinate many physiological functions. First identified more than a century ago on the basis of their readily discernible secretory granules by routine histology, these cells are located at the base of the crypts of Lieberkuhn, tiny invaginations that line the mucosal surface all along the small intestine. Investigations over the past several decades determined that these cells synthesize and secrete substantial quantities of antimicrobial peptides and proteins. More recent studies have determined that these antimicrobial molecules are key mediators of host-microbe interactions, including homeostatic balance with colonizing microbiota and innate immune protection from enteric pathogens. Perhaps more intriguing, Paneth cells secrete factors that help sustain and modulate the epithelial stem and progenitor cells that cohabitate in the crypts and rejuvenate the small intestinal epithelium. Dysfunction of Paneth cell biology contributes to the pathogenesis of chronic inflammatory bowel disease., Paneth cells are highly specialized epithelial cells of the small intestine, where they coordinate many physiological functions. First identified more than a century ago on the basis of their readily discernible secretory granules by routine histology, these cells are located at the base of the crypts of Lieberkuhn, tiny invaginations that line the mucosal surface all along the small intestine. Investigations over the past several decades determined that these cells synthesize and secrete substantial quantities of antimicrobial peptides and proteins. More recent studies have determined that these antimicrobial molecules are key mediators of host-microbe interactions, including homeostatic balance with colonizing microbiota and innate immune protection from enteric pathogens. Perhaps more intriguing, Paneth cells secrete factors that help sustain and modulate the epithelial stem and progenitor cells that cohabitate in the crypts and rejuvenate the small intestinal epithelium. Dysfunction of Paneth cell biology contributes to the pathogenesis of chronic inflammatory bowel disease.

Published
2013

19. DNA methylation dynamics during intestinal stem cell differentiation reveals enhancers driving gene expression in the villus

Author

Kaaij, L.T., van de Wetering, M., Fang, F., Decato, B., Molaro, A., van de Werken, H.J., van Es, J.H., Schuijers, J., de Wit, E., de Laat, W., Hannon, G.J., Clevers, H.C., Smith, A.D., Ketting, R.F., Kaaij, L.T., van de Wetering, M., Fang, F., Decato, B., Molaro, A., van de Werken, H.J., van Es, J.H., Schuijers, J., de Wit, E., de Laat, W., Hannon, G.J., Clevers, H.C., Smith, A.D., and Ketting, R.F.

Abstract

BACKGROUND: DNA methylation is of pivotal importance during development. Previous genome-wide studies identified numerous differentially methylated regions upon differentiation of stem cells, many of them associated with transcriptional start sites. RESULTS: We present the first genome-wide, single-base-resolution view into DNA methylation dynamics during differentiation of a mammalian epithelial stem cell: the mouse small intestinal Lgr5+ stem cell. Very little change was observed at transcriptional start sites and our data suggest that differentiation-related genes are already primed for expression in the stem cell. Genome-wide, only 50 differentially methylated regions were identified. Almost all of these loci represent enhancers driving gene expression in the differentiated part of the small intestine. Finally, we show that binding of the transcription factor Tcf4 correlates with hypo-methylation and demonstrate that Tcf4 is one of the factors contributing to formation of differentially methylated regions. CONCLUSIONS: Our results reveal limited DNA methylation dynamics during small intestine stem cell differentiation and an impact of transcription factor binding on shaping the DNA methylation landscape during differentiation of stem cells in vivo., BACKGROUND: DNA methylation is of pivotal importance during development. Previous genome-wide studies identified numerous differentially methylated regions upon differentiation of stem cells, many of them associated with transcriptional start sites. RESULTS: We present the first genome-wide, single-base-resolution view into DNA methylation dynamics during differentiation of a mammalian epithelial stem cell: the mouse small intestinal Lgr5+ stem cell. Very little change was observed at transcriptional start sites and our data suggest that differentiation-related genes are already primed for expression in the stem cell. Genome-wide, only 50 differentially methylated regions were identified. Almost all of these loci represent enhancers driving gene expression in the differentiated part of the small intestine. Finally, we show that binding of the transcription factor Tcf4 correlates with hypo-methylation and demonstrate that Tcf4 is one of the factors contributing to formation of differentially methylated regions. CONCLUSIONS: Our results reveal limited DNA methylation dynamics during small intestine stem cell differentiation and an impact of transcription factor binding on shaping the DNA methylation landscape during differentiation of stem cells in vivo.

Published
2013

20. ChIPping away at intestinal stemness

Author

Child Health, Hubrecht Institute with UMC, Cancer, Regenerative Medicine and Stem Cells, Clevers, H.C., Schuijers, J., Child Health, Hubrecht Institute with UMC, Cancer, Regenerative Medicine and Stem Cells, Clevers, H.C., and Schuijers, J.

Published
2013

21. Generation and exploitation of stem cell derived organoid cultures

Author

Child Health, Hubrecht Institute with UMC, Cancer, Regenerative Medicine and Stem Cells, Clevers, H.C., Karthaus, W.R., Child Health, Hubrecht Institute with UMC, Cancer, Regenerative Medicine and Stem Cells, Clevers, H.C., and Karthaus, W.R.

Published
2013

25. The R-spondin protein family

Author

de Lau, W.B.M., Snel, B., Clevers, H.C., de Lau, W.B.M., Snel, B., and Clevers, H.C.

Abstract

The four vertebrate R-spondin proteins are secreted agonists of the canonical Wnt/beta-catenin signaling pathway. These proteins are approximately 35 kDa, and are characterized by two amino-terminal furin-like repeats, which are necessary and sufficient for Wnt signal potentiation, and a thrombospondin domain situated more towards the carboxyl terminus that can bind matrix glycosaminoglycans and/or proteoglycans. Although R-spondins are unable to initiate Wnt signaling, they can potently enhance responses to low-dose Wnt proteins. In humans, rare disruptions of the gene encoding R-spondin1 cause a syndrome of XX sex reversal (phenotypic male), palmoplantar keratosis (a thickening of the palms and soles caused by excess keratin formation) and predisposition to squamous cell carcinoma of the skin. Mutations in the gene encoding R-spondin4 cause anonychia (absence or hypoplasia of nails on fingers and toes). Recently, leucine-rich repeat-containing G-protein-coupled receptor (Lgr)4, Lgr5 and Lgr6, three closely related orphans of the leucine-rich repeat family of G-protein-coupled receptors, have been identified as receptors for R-spondins. Lgr5 and Lgr6 are markers for adult stem cells. Because R-spondins are potent stimulators of adult stem cell proliferation in vivo and in vitro, these findings might guide the therapeutic use of R-spondins in regenerative medicine., The four vertebrate R-spondin proteins are secreted agonists of the canonical Wnt/beta-catenin signaling pathway. These proteins are approximately 35 kDa, and are characterized by two amino-terminal furin-like repeats, which are necessary and sufficient for Wnt signal potentiation, and a thrombospondin domain situated more towards the carboxyl terminus that can bind matrix glycosaminoglycans and/or proteoglycans. Although R-spondins are unable to initiate Wnt signaling, they can potently enhance responses to low-dose Wnt proteins. In humans, rare disruptions of the gene encoding R-spondin1 cause a syndrome of XX sex reversal (phenotypic male), palmoplantar keratosis (a thickening of the palms and soles caused by excess keratin formation) and predisposition to squamous cell carcinoma of the skin. Mutations in the gene encoding R-spondin4 cause anonychia (absence or hypoplasia of nails on fingers and toes). Recently, leucine-rich repeat-containing G-protein-coupled receptor (Lgr)4, Lgr5 and Lgr6, three closely related orphans of the leucine-rich repeat family of G-protein-coupled receptors, have been identified as receptors for R-spondins. Lgr5 and Lgr6 are markers for adult stem cells. Because R-spondins are potent stimulators of adult stem cell proliferation in vivo and in vitro, these findings might guide the therapeutic use of R-spondins in regenerative medicine.

Published
2012

26. Characterizing intestinal stem cells. An important part of the puzzle

Author

Child Health, Hubrecht Institute with UMC, Cancer, Regenerative Medicine and Stem Cells, Clevers, H.C., Schepers, A.G.A.P., Child Health, Hubrecht Institute with UMC, Cancer, Regenerative Medicine and Stem Cells, Clevers, H.C., and Schepers, A.G.A.P.

Published
2012

28. Cdx genes and the maitenance of tissue progenitors in the mouse

Author

Hubrecht Institute with UMC, Cancer, Regenerative Medicine and Stem Cells, Clevers, H.C., Deschamps, J., Bialecka, M., Hubrecht Institute with UMC, Cancer, Regenerative Medicine and Stem Cells, Clevers, H.C., Deschamps, J., and Bialecka, M.

Published
2012

29. Sequence-specific high mobility group box factors recognize 10-12-base pair minor groove motifs

Author

van Beest, M., Dooijes, D., van de Wetering, M.L., Kjearulff, S., Bonvin, A.M.J.J., Nielsen, O., Clevers, H.C., NMR-spectroscopie, and NMR Spectroscopy 1

Subjects
International, Taverne
Abstract

Sequence-specific high mobility group (HMG) box factors bind and bend DNA via interactions in the minor groove. Three-dimensional NMR analyses have provided the structural basis for this interaction. The cognate HMG domain DNA motif is generally believed to span 6-8 bases. However, alignment of promoter elements controlled by the yeast genes ste11 and Rox1 has indicated strict conservation of a larger DNA motif. By site selection, we identify a highly specific 12-base pair motif for Ste11, AGAACAAAGAAA. Similarly, we show that Tcf1, MatMc, and Sox4 bind unique, highly specific DNA motifs of 12, 12, and 10 base pairs, respectively. Footprinting with a deletion mutant of Ste11 reveals a novel interaction between the 3' base pairs of the extended DNA motif and amino acids C-terminal to the HMG domain. The sequence-specific interaction of Ste11 with these 3' base pairs contributes significantly to binding and bending of the DNA motif.

Published
2000

34. Cdx, Hox and the genetics of axial extension in the mouse

Author

Hubrecht Institute with UMC, Cancer, Regenerative Medicine and Stem Cells, Clevers, H.C., Deschamps, J., van de Ven, C., Hubrecht Institute with UMC, Cancer, Regenerative Medicine and Stem Cells, Clevers, H.C., Deschamps, J., and van de Ven, C.

Published
2011

37. Unraveling the Wnt secretion pathway

Author

Hubrecht Institute with UMC, Cancer, Clevers, H.C., Korswagen, H.C., Harterink, M., Hubrecht Institute with UMC, Cancer, Clevers, H.C., Korswagen, H.C., and Harterink, M.

Published
2011

40. Growth of the zebrafish heart

Author

Clevers, H.C., Bakkers, J., de Pater, E.M., Clevers, H.C., Bakkers, J., and de Pater, E.M.

Published
2010

48. Growth of the zebrafish heart

Author

Child Health, Hubrecht Institute with UMC, Cancer, Regenerative Medicine and Stem Cells, Clevers, H.C., Bakkers, J., de Pater, E.M., Child Health, Hubrecht Institute with UMC, Cancer, Regenerative Medicine and Stem Cells, Clevers, H.C., Bakkers, J., and de Pater, E.M.

Published
2010

49. Double-strand break repair and G4 DNA stability in Caenorhabditis elegans

Author

Child Health, Hubrecht Institute with UMC, Cancer, Regenerative Medicine and Stem Cells, Clevers, H.C., Tijsterman, M., Pontier, D.B., Child Health, Hubrecht Institute with UMC, Cancer, Regenerative Medicine and Stem Cells, Clevers, H.C., Tijsterman, M., and Pontier, D.B.

Published
2010

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