Hans Clevers



  1. Clevers H, Nusse R. Wnt/?-catenin signaling and disease. Cell. 2012;149:1192-205 pubmed publisher
    ..In this Review, we provide an update of the core Wnt/?-catenin signaling pathway, discuss how its various components contribute to disease, and pose outstanding questions to be addressed in the future. ..
  2. Weeber F, van de Wetering M, Hoogstraat M, Dijkstra K, Krijgsman O, Kuilman T, et al. Preserved genetic diversity in organoids cultured from biopsies of human colorectal cancer metastases. Proc Natl Acad Sci U S A. 2015;112:13308-11 pubmed publisher
    ..These findings support further exploration of patient-derived organoids as an ex vivo platform to personalize anticancer treatment. ..
  3. Zhou J, Li C, Sachs N, Chiu M, Wong B, Chu H, et al. Differentiated human airway organoids to assess infectivity of emerging influenza virus. Proc Natl Acad Sci U S A. 2018;115:6822-6827 pubmed publisher
    ..These differentiated airway organoids can be applied for rapid assessment of the infectivity of emerging respiratory viruses to human. ..
  4. van Andel H, Ren Z, Koopmans I, Joosten S, Kocemba K, de Lau W, et al. Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins. Proc Natl Acad Sci U S A. 2017;114:376-381 pubmed publisher
    ..These results advocate targeting of the LGR4/R-spondin interaction as a therapeutic strategy in MM. ..
  5. Fumagalli A, Drost J, Suijkerbuijk S, van Boxtel R, de Ligt J, Offerhaus G, et al. Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids. Proc Natl Acad Sci U S A. 2017;114:E2357-E2364 pubmed publisher
    ..Our findings imply that the ability to metastasize-i.e., to colonize distant sites-is the direct consequence of the loss of dependency on specific niche signals. ..
  6. Schneeberger K, Vogel G, Teunissen H, van Ommen D, Begthel H, El Bouazzaoui L, et al. An inducible mouse model for microvillus inclusion disease reveals a role for myosin Vb in apical and basolateral trafficking. Proc Natl Acad Sci U S A. 2015;112:12408-13 pubmed publisher
    ..This includes severe diarrhea, loss of microvilli, occurrence of microvillus inclusions, and subapical secretory granules. Thus, loss of MYO5B disturbs both apical and basolateral trafficking of proteins and causes MVID in mice. ..
  7. Koo B, van Es J, van den Born M, Clevers H. Porcupine inhibitor suppresses paracrine Wnt-driven growth of Rnf43;Znrf3-mutant neoplasia. Proc Natl Acad Sci U S A. 2015;112:7548-50 pubmed publisher
    ..These results establish that paracrine Wnt secretion is an essential driver of RZ(-/-) tumor growth and imply that a therapeutic window exists for the use of porcupine inhibitors for RZ-mutant cancers. ..
  8. Sasaki N, Clevers H. Studying cellular heterogeneity and drug sensitivity in colorectal cancer using organoid technology. Curr Opin Genet Dev. 2018;52:117-122 pubmed publisher
    ..Finally, we address the exciting recent results that show that tumor organoid technology is highly predictive for drug response in metastatic colorectal cancer. ..
  9. Heo I, Dutta D, Schaefer D, Iakobachvili N, Artegiani B, Sachs N, et al. Modelling Cryptosporidium infection in human small intestinal and lung organoids. Nat Microbiol. 2018;3:814-823 pubmed publisher
    ..Our study presents organoids as a physiologically relevant in vitro model system to study Cryptosporidium infection. ..

More Information


  1. Huch M, Gehart H, van Boxtel R, Hamer K, Blokzijl F, Verstegen M, et al. Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell. 2015;160:299-312 pubmed publisher
    ..Clonal long-term expansion of primary adult liver stem cells opens up experimental avenues for disease modeling, toxicology studies, regenerative medicine, and gene therapy. ..
  2. Beumer J, Artegiani B, Post Y, Reimann F, Gribble F, Nguyen T, et al. Enteroendocrine cells switch hormone expression along the crypt-to-villus BMP signalling gradient. Nat Cell Biol. 2018;20:909-916 pubmed publisher
    ..These findings establish alternative strategies to target EECs with therapeutically relevant hormone production through BMP modulation. ..
  3. van de Wetering M, Francies H, FRANCIS J, Bounova G, Iorio F, Pronk A, et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell. 2015;161:933-45 pubmed publisher
    ..Organoid technology may fill the gap between cancer genetics and patient trials, complement cell-line- and xenograft-based drug studies, and allow personalized therapy design. PAPERCLIP. ..
  4. Schuijers J, van der Flier L, van Es J, Clevers H. Robust cre-mediated recombination in small intestinal stem cells utilizing the olfm4 locus. Stem Cell Reports. 2014;3:234-41 pubmed publisher
    ..The eGFPCreERT2 fusion protein faithfully marks all stem cells in the small intestine and induces the activation of a conditional LacZ reporter with robust efficiency. ..
  5. Roerink S, Sasaki N, Lee Six H, Young M, Alexandrov L, Behjati S, et al. Intra-tumour diversification in colorectal cancer at the single-cell level. Nature. 2018;556:457-462 pubmed publisher
  6. Karthaus W, Iaquinta P, Drost J, Gracanin A, van Boxtel R, Wongvipat J, et al. Identification of multipotent luminal progenitor cells in human prostate organoid cultures. Cell. 2014;159:163-175 pubmed publisher
    ..These data support a luminal multilineage progenitor cell model for prostate tissue and establish a robust, scalable system for mechanistic studies. ..
  7. Gehart H, Clevers H. Repairing organs: lessons from intestine and liver. Trends Genet. 2015;31:344-51 pubmed publisher
    ..Here we discuss how the growing tool set of stem cell biology can bring organ repair from fictitious narrative to medical practice. ..
  8. Tetteh P, Farin H, Clevers H. Plasticity within stem cell hierarchies in mammalian epithelia. Trends Cell Biol. 2015;25:100-8 pubmed publisher
    ..In this review, we discuss recent examples of such plasticity in selected mammalian epithelia, highlighting the different modes of regeneration and their implications for our understanding of cellular hierarchy and tissue self-renewal. ..
  9. Koo B, Clevers H. Stem cells marked by the R-spondin receptor LGR5. Gastroenterology. 2014;147:289-302 pubmed publisher
    ..This review describes the rediscovery of crypt base columnar cells as LGR5(+) adult stem cells and summarizes subsequent progress, promises, unresolved issues, and challenges of the field. ..
  10. Boj S, Hwang C, Baker L, Chio I, Engle D, Corbo V, et al. Organoid models of human and mouse ductal pancreatic cancer. Cell. 2015;160:324-38 pubmed publisher
    ..The confirmation of many of these protein changes in human tissues demonstrates that organoids are a facile model system to discover characteristics of this deadly malignancy. ..
  11. Drost J, Artegiani B, Clevers H. The Generation of Organoids for Studying Wnt Signaling. Methods Mol Biol. 2016;1481:141-59 pubmed publisher
    ..Moreover, we provide a detailed protocol for lentiviral transduction and CRISPR/Cas9-mediated genome modification of organoid cultures. ..
  12. Tetteh P, Basak O, Farin H, Wiebrands K, Kretzschmar K, Begthel H, et al. Replacement of Lost Lgr5-Positive Stem Cells through Plasticity of Their Enterocyte-Lineage Daughters. Cell Stem Cell. 2016;18:203-13 pubmed publisher
    ..We conclude that the highly proliferative, short-lived enterocyte precursors serve as a large reservoir of potential stem cells during crypt regeneration. ..
  13. Drost J, Clevers H. Who Is in the Driver's Seat: Tracing Cancer Genes Using CRISPR-Barcoding. Mol Cell. 2016;63:352-4 pubmed publisher
    ..In this issue, Guernet et al. (2016) devised clustered regularly interspaced short palindromic repeats (CRISPR)-barcoding to functionally annotate specific mutations and study clonal evolution in heterogeneous cell populations. ..
  14. Clevers H, Watt F. Defining Adult Stem Cells by Function, not by Phenotype. Annu Rev Biochem. 2018;87:1015-1027 pubmed publisher
    ..While certain key housekeeping and developmental signaling pathways are shared between different stem cell systems, there may be no general, deeper principles underlying the renewal mechanisms of the various individual tissues. ..
  15. Dutta D, Clevers H. Organoid culture systems to study host-pathogen interactions. Curr Opin Immunol. 2017;48:15-22 pubmed publisher
    ..Here we discuss the most recent and striking studies on host-microbe interactions in organoid cultures, highlighting various methods which can be used for developing microbe-organoid co-culture systems. ..
  16. Driehuis E, Clevers H. CRISPR/Cas 9 genome editing and its applications in organoids. Am J Physiol Gastrointest Liver Physiol. 2017;312:G257-G265 pubmed publisher
    ..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. ..
  17. Boj S, Vonk A, Statia M, Su J, Vries R, Beekman J, et al. Forskolin-induced Swelling in Intestinal Organoids: An In Vitro Assay for Assessing Drug Response in Cystic Fibrosis Patients. J Vis Exp. 2017;: pubmed publisher
    ..This assay provides a cost-effective approach for the identification of drug-responsive individuals, independent of their CFTR mutations. It may also be instrumental in the development of future CFTR modulators. ..
  18. Sachs N, Tsukamoto Y, Kujala P, Peters P, Clevers H. Intestinal epithelial organoids fuse to form self-organizing tubes in floating collagen gels. Development. 2017;144:1107-1112 pubmed publisher
    ..Thus, the remarkable self-organizing properties of Lgr5+ stem cells extend beyond the level of the microscopic cystic organoid to the next, macroscopic, level of tube formation. ..
  19. Dutta D, Heo I, Clevers H. Disease Modeling in Stem Cell-Derived 3D Organoid Systems. Trends Mol Med. 2017;23:393-410 pubmed publisher
    ..We discuss recent advances in the application of organoids in studying cancer and hereditary diseases, as well as in the examination of host cell-microorganism interactions. ..
  20. Schutgens F, Rookmaaker M, Blokzijl F, van Boxtel R, Vries R, Cuppen E, et al. Troy/TNFRSF19 marks epithelial progenitor cells during mouse kidney development that continue to contribute to turnover in adult kidney. Proc Natl Acad Sci U S A. 2017;114:E11190-E11198 pubmed publisher
    ..Our data show that Troy marks a renal stem/progenitor cell population in the developing kidney that in adult kidney contributes to homeostasis, predominantly of the collecting duct, and regeneration. ..
  21. Sachs N, de Ligt J, Kopper O, Gogola E, Bounova G, Weeber F, et al. A Living Biobank of Breast Cancer Organoids Captures Disease Heterogeneity. Cell. 2018;172:373-386.e10 pubmed publisher
    ..This study describes a representative collection of well-characterized BC organoids available for cancer research and drug development, as well as a strategy to assess in vitro drug response in a personalized fashion. ..
  22. Cristobal A, van den Toorn H, van de Wetering M, Clevers H, Heck A, Mohammed S. Personalized Proteome Profiles of Healthy and Tumor Human Colon Organoids Reveal Both Individual Diversity and Basic Features of Colorectal Cancer. Cell Rep. 2017;18:263-274 pubmed publisher
    ..We demonstrate that a personalized patient-specific organoid proteome profile can be related to the diagnosis of a patient and with future development contribute to the generation of personalized therapies. ..
  23. request reprint
    Beumer J, Clevers H. Regulation and plasticity of intestinal stem cells during homeostasis and regeneration. Development. 2016;143:3639-3649 pubmed
    ..Nutritional state and inflammation have been recently identified as upstream regulators of stem cell activity in the mammalian intestine, and we explore how these systemic signals can influence homeostasis and regeneration. ..
  24. Tetteh P, Kretzschmar K, Begthel H, van den Born M, Korving J, Morsink F, et al. Generation of an inducible colon-specific Cre enzyme mouse line for colon cancer research. Proc Natl Acad Sci U S A. 2016;113:11859-11864 pubmed
    ..Our results establish the Car1CreER KI as a valuable mouse model to study colon-specific tumorigenesis and metastasis as well as cancer-cell-of-origin questions. ..
  25. Clevers H. Modeling Development and Disease with Organoids. Cell. 2016;165:1586-1597 pubmed publisher
    ..Organoids open up new avenues for regenerative medicine and, in combination with editing technology, for gene therapy. The many potential applications of this technology are only beginning to be explored. ..
  26. Schwank G, Clevers H. CRISPR/Cas9-Mediated Genome Editing of Mouse Small Intestinal Organoids. Methods Mol Biol. 2016;1422:3-11 pubmed publisher
    ..This protocol allows the study of gene function in intestinal epithelial homeostasis and pathophysiology and can be extended to epithelial organoids derived from other internal mouse and human organs. ..
  27. Clevers H. The intestinal crypt, a prototype stem cell compartment. Cell. 2013;154:274-84 pubmed publisher
    ..These studies are filling in the outlines of a robust homeostatic self-renewal process that defies some of the classical definitions of stem cell behavior, such as asymmetric division, quiescence, and exhaustion. ..
  28. Artegiani B, Lyubimova A, Muraro M, van Es J, van Oudenaarden A, Clevers H. A Single-Cell RNA Sequencing Study Reveals Cellular and Molecular Dynamics of the Hippocampal Neurogenic Niche. Cell Rep. 2017;21:3271-3284 pubmed publisher
    ..The combined data constitute a valuable resource to understand regulatory mechanisms of adult neurogenesis. ..
  29. Kretzschmar K, Clevers H. Organoids: Modeling Development and the Stem Cell Niche in a Dish. Dev Cell. 2016;38:590-600 pubmed publisher
    ..Here we discuss how organoid cultures of the intestine and other tissues have been established and how they are utilized as an in vitro model system for stem cell research and developmental biology. ..
  30. Barbosa F, Xiao Y, Bian F, Coursey T, Ko B, Clevers H, et al. Goblet Cells Contribute to Ocular Surface Immune Tolerance-Implications for Dry Eye Disease. Int J Mol Sci. 2017;18: pubmed publisher
    ..GC loss may contribute to the abrogation of ocular surface immune tolerance that is observed in dry eye. ..
  31. Clevers H. The cancer stem cell: premises, promises and challenges. Nat Med. 2011;17:313-9 pubmed publisher
    ..This review attempts to summarize the underlying concepts of this notion, to distinguish hard facts from beliefs and to define the future challenges of the field. ..
  32. Sasaki N, Sachs N, Wiebrands K, Ellenbroek S, Fumagalli A, Lyubimova A, et al. Reg4+ deep crypt secretory cells function as epithelial niche for Lgr5+ stem cells in colon. Proc Natl Acad Sci U S A. 2016;113:E5399-407 pubmed publisher
    ..DCS cells can be massively produced from Lgr5(+) colon stem cells in vitro by combined Notch inhibition and Wnt activation. We conclude that Reg4(+) DCS cells serve as Paneth cell equivalents in the colon crypt niche. ..
  33. Schuijers J, Junker J, Mokry M, Hatzis P, Koo B, Sasselli V, et al. Ascl2 acts as an R-spondin/Wnt-responsive switch to control stemness in intestinal crypts. Cell Stem Cell. 2015;16:158-70 pubmed publisher
    ..In turn, Ascl2, together with β-catenin/Tcf, activates the genes fundamental to the stem cell state. In this manner, Ascl2 forms a transcriptional switch that is both Wnt responsive and Wnt dependent to define stem cell identity. ..
  34. Kretzschmar K, Clevers H. Wnt/?-catenin signaling in adult mammalian epithelial stem cells. Dev Biol. 2017;428:273-282 pubmed publisher
    ..We further highlight the research that led to the identification of new stem cell markers and methods to study adult stem cells ex vivo. ..
  35. Basak O, Beumer J, Wiebrands K, Seno H, van Oudenaarden A, Clevers H. Induced Quiescence of Lgr5+ Stem Cells in Intestinal Organoids Enables Differentiation of Hormone-Producing Enteroendocrine Cells. Cell Stem Cell. 2017;20:177-190.e4 pubmed publisher
    ..Our observations uncouple Wnt-dependent stem cell maintenance from EGF-dependent proliferation and provide an approach for the study of the elusive EECs in a defined environment. ..
  36. Farin H, Karthaus W, Kujala P, Rakhshandehroo M, Schwank G, Vries R, et al. Paneth cell extrusion and release of antimicrobial products is directly controlled by immune cell-derived IFN-?. J Exp Med. 2014;211:1393-405 pubmed publisher
    ..The identification of IFN-? as a trigger for degranulation and extrusion of PCs establishes a novel effector mechanism by which immune responses may regulate epithelial status and the gut microbiome. ..
  37. Clevers H, Bevins C. Paneth cells: maestros of the small intestinal crypts. Annu Rev Physiol. 2013;75:289-311 pubmed publisher
    ..Dysfunction of Paneth cell biology contributes to the pathogenesis of chronic inflammatory bowel disease...
  38. Beumer J, Clevers H. How the Gut Feels, Smells, and Talks. Cell. 2017;170:10-11 pubmed publisher
    ..In this issue of Cell, Bellono and colleagues identify a variety of luminal stimuli acting on serotonin-secreting enteroendocrine cells and, for the first time, demonstrate a functional synaptic interaction with neurons. ..