Cited by 1453D Printing in Biomedical ResearchCancer Cells and MetastasisTissue Engineering and Regenerative Medicine

Organoids in gastrointestinal diseases: From experimental models to clinical translation

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Günther, Claudia, Winner, Beate, Neurath, Markus F, Stappenbeck, Thaddeus S·2022·Gut

Abstract

We are entering an era of medicine where increasingly sophisticated data will be obtained from patients to determine proper diagnosis, predict outcomes and direct therapies. We predict that the most valuable data will be produced by systems that are highly dynamic in both time and space. Three-dimensional (3D) organoids are poised to be such a highly valuable system for a variety of gastrointestinal (GI) diseases. In the lab, organoids have emerged as powerful systems to model molecular and cellular processes orchestrating natural and pathophysiological human tissue formation in remarkable detail. Preclinical studies have impressively demonstrated that these organs-in-a-dish can be used to model immunological, neoplastic, metabolic or infectious GI disorders by taking advantage of patient-derived material. Technological breakthroughs now allow to study cellular communication and molecular mechanisms of interorgan cross-talk in health and disease including communication along for example, the gut–brain axis or gut–liver axis. Despite considerable success in culturing classical 3D organoids from various parts of the GI tract, some challenges remain to develop these systems to best help patients. Novel platforms such as organ-on-a-chip, engineered biomimetic systems including engineered organoids, micromanufacturing, bioprinting and enhanced rigour and reproducibility will open improved avenues for tissue engineering, as well as regenerative and personalised medicine. This review will highlight some of the established methods and also some exciting novel perspectives on organoids in the fields of gastroenterology. At present, this field is poised to move forward and impact many currently intractable GI diseases in the form of novel diagnostics and therapeutics.

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  1. [2]Kretzschmar K, Clevers H. Organoids: modeling development and the stem cell niche in a dish. Dev Cell 2016; 38: 590– 600. 10.1016/j.devcel.2016.08.014 27676432 · DOI
  2. [3]Rossi G, Manfrin A, Lutolf MP. Progress and potential in organoid research. Nat Rev Genet 2018; 19: 671– 87. 10.1038/s41576-018-0051-9 30228295 · DOI · Paper page
  3. [8]Huch M, Dorrell C, Boj SF, et al. In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature 2013; 494: 247– 50. 10.1038/nature11826 23354049 PMC3634804 · DOI · Paper page
  4. [9]Lugli N, Kamileri I, Keogh A, et al. R-spondin 1 and noggin facilitate expansion of resident stem cells from non-damaged gallbladders. EMBO Rep 2016; 17: 769– 79. 10.15252/embr.201642169 26993089 PMC5341509 · DOI
  5. [10]Boj SF, Hwang C-I, Baker LA, et al. Organoid models of human and mouse ductal pancreatic cancer. Cell 2015; 160: 324– 38. 10.1016/j.cell.2014.12.021 25557080 PMC4334572 · DOI · Paper page
  6. [11]Huch M, Bonfanti P, Boj SF, et al. Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis. Embo J 2013; 32: 2708– 21. 10.1038/emboj.2013.204 24045232 PMC3801438 · DOI
  7. [12]Fordham RP, Yui S, Hannan NRF, et al. Transplantation of expanded fetal intestinal progenitors contributes to colon regeneration after injury. Cell Stem Cell 2013; 13: 734– 44. 10.1016/j.stem.2013.09.015 24139758 PMC3858813 · DOI
  8. [13]Schreurs RRCE, Baumdick ME, Sagebiel AF, et al. Human Fetal TNF-α-Cytokine-Producing CD4+ Effector Memory T Cells Promote Intestinal Development and Mediate Inflammation Early in Life. Immunity 2019; 50: 462– 76. 10.1016/j.immuni.2018.12.010 30770246 · DOI
  9. [15]Takeda N, Jain R, LeBoeuf MR, et al. Interconversion between intestinal stem cell populations in distinct niches. Science 2011; 334: 1420– 4. 10.1126/science.1213214 22075725 PMC3705713 · DOI · Paper page
  10. [16]Brittan M, Wright NA. Stem cell in gastrointestinal structure and neoplastic development. Gut 2004; 53: 899– 910. 10.1136/gut.2003.025478 15138220 PMC1774081 · DOI
  11. [17]Barker N, Huch M, Kujala P, et al. Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell 2010; 6: 25– 36. 10.1016/j.stem.2009.11.013 20085740 · DOI · Paper page
  12. [18]van der Flier LG, Clevers H. Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu Rev Physiol 2009; 71: 241– 60. 10.1146/annurev.physiol.010908.163145 18808327 · DOI
  13. [19]Manohar R, Komori J, Guzik L, et al. Identification and expansion of a unique stem cell population from adult mouse gallbladder. Hepatology 2011; 54: 1830– 41. 10.1002/hep.24568 21793026 PMC3205206 · DOI
  14. [21]Norkin M, Ordóñez-Morán P, Huelsken J. High-content, targeted RNA-seq screening in organoids for drug discovery in colorectal cancer. Cell Rep 2021; 35: 109026. 10.1016/j.celrep.2021.109026 33882314 · DOI
  15. [22]Haber AL, Biton M, Rogel N, et al. A single-cell survey of the small intestinal epithelium. Nature 2017; 551: 333– 9. 10.1038/nature24489 29144463 PMC6022292 · DOI · Paper page
  16. [23]Beumer J, Puschhof J, Bauzá-Martinez J, et al. High-Resolution mRNA and secretome atlas of human enteroendocrine cells. Cell 2020; 181: 1291– 306. 10.1016/j.cell.2020.04.036 32407674 · DOI
  17. [24]Spence JR, Mayhew CN, Rankin SA, et al. Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature 2011; 470: 105– 9. 10.1038/nature09691 21151107 PMC3033971 · DOI
  18. [27]VanDussen KL, Marinshaw JM, Shaikh N, et al. Development of an enhanced human gastrointestinal epithelial culture system to facilitate patient-based assays. Gut 2015; 64: 911– 20. 10.1136/gutjnl-2013-306651 25007816 PMC4305344 · DOI · Paper page
  19. [28]Dotti I, Mora-Buch R, Ferrer-Picón E, et al. Alterations in the epithelial stem cell compartment could contribute to permanent changes in the mucosa of patients with ulcerative colitis. Gut 2017; 66: 2069– 79. 10.1136/gutjnl-2016-312609 27803115 PMC5749340 · DOI
  20. [29]Howell KJ, Kraiczy J, Nayak KM, et al. DNA Methylation and Transcription Patterns in Intestinal Epithelial Cells From Pediatric Patients With Inflammatory Bowel Diseases Differentiate Disease Subtypes and Associate With Outcome. Gastroenterology 2018; 154: 585– 98. 10.1053/j.gastro.2017.10.007 29031501 PMC6381389 · DOI
  21. [30]Suzuki K, Murano T, Shimizu H, et al. Single cell analysis of Crohn's disease patient-derived small intestinal organoids reveals disease activity-dependent modification of stem cell properties. J Gastroenterol 2018; 53: 1035– 47. 10.1007/s00535-018-1437-3 29374777 PMC6132922 · DOI
  22. [31]Kraiczy J, Nayak KM, Howell KJ, et al. DNA methylation defines regional identity of human intestinal epithelial organoids and undergoes dynamic changes during development. Gut 2019; 68: 49– 61. 10.1136/gutjnl-2017-314817 29141958 PMC6839835 · DOI
  23. [32]Nanki K, Toshimitsu K, Takano A, et al. Divergent routes toward Wnt and R-spondin niche Independency during human gastric carcinogenesis. Cell 2018; 174: 856– 69. 10.1016/j.cell.2018.07.027 30096312 · DOI
  24. [33]Koike H, Iwasawa K, Ouchi R, et al. Engineering human hepato-biliary-pancreatic organoids from pluripotent stem cells. Nat Protoc 2021; 16: 919– 36. 10.1038/s41596-020-00441-w 33432231 PMC8212777 · DOI
  25. [34]Collin de l'Hortet A, Takeishi K, Guzman-Lepe J, et al. Generation of human fatty livers using Custom-Engineered induced pluripotent stem cells with modifiable SIRT1 metabolism. Cell Metab 2019; 30: 385– 401. 10.1016/j.cmet.2019.06.017 31390551 PMC6691905 · DOI
  26. [35]Koike H, Iwasawa K, Ouchi R, et al. Modelling human hepato-biliary-pancreatic organogenesis from the foregut-midgut boundary. Nature 2019; 574: 112– 6. 10.1038/s41586-019-1598-0 31554966 PMC7643931 · DOI · Paper page
  27. [36]Camp JG, Sekine K, Gerber T, et al. Multilineage communication regulates human liver bud development from pluripotency. Nature 2017; 546: 533– 8. 10.1038/nature22796 28614297 · DOI · Paper page
  28. [37]Hendriks D, Artegiani B, Hu H, et al. Establishment of human fetal hepatocyte organoids and CRISPR-Cas9-based gene knockin and knockout in organoid cultures from human liver. Nat Protoc 2021; 16: 182– 217. 10.1038/s41596-020-00411-2 33247284 · DOI
  29. [39]McCracken KW, Howell JC, Wells JM, et al. Generating human intestinal tissue from pluripotent stem cells in vitro. Nat Protoc 2011; 6: 1920– 8. 10.1038/nprot.2011.410 22082986 PMC3896236 · DOI
  30. [40]Ouchi R, Togo S, Kimura M, et al. Modeling steatohepatitis in humans with pluripotent stem cell-derived organoids. Cell Metab 2019; 30: 374– 84. 10.1016/j.cmet.2019.05.007 31155493 PMC6687537 · DOI · Paper page
  31. [41]Wiedenmann S, Breunig M, Merkle J, et al. Single-cell-resolved differentiation of human induced pluripotent stem cells into pancreatic duct-like organoids on a microwell chip. Nat Biomed Eng 2021; 5: 897– 913. 10.1038/s41551-021-00757-2 34239116 PMC7611572 · DOI
  32. [42]Forster R, Chiba K, Schaeffer L, et al. Human intestinal tissue with adult stem cell properties derived from pluripotent stem cells. Stem Cell Reports 2014; 2: 838– 52. 10.1016/j.stemcr.2014.05.001 24936470 PMC4050346 · DOI
  33. [43]Sarvestani SK, Signs S, Hu B, et al. Induced organoids derived from patients with ulcerative colitis recapitulate colitic reactivity. Nat Commun 2021; 12: 262. 10.1038/s41467-020-20351-5 33431859 PMC7801686 · DOI
  34. [45]Rowe RG, Daley GQ. Induced pluripotent stem cells in disease modelling and drug discovery. Nat Rev Genet 2019; 20: 377– 88. 10.1038/s41576-019-0100-z 30737492 PMC6584039 · DOI
  35. [46]Neurath MF. Cytokines in inflammatory bowel disease. Nat Rev Immunol 2014; 14: 329– 42. 10.1038/nri3661 24751956 · DOI · Paper page
  36. [48]Schreurs RRCE, Baumdick ME, Drewniak A, et al. In vitro co-culture of human intestinal organoids and lamina propria-derived CD4+ T cells. STAR Protoc 2021; 2: 100519. 10.1016/j.xpro.2021.100519 34036282 PMC8138864 · DOI
  37. [49]Cattaneo CM, Dijkstra KK, Fanchi LF, et al. Tumor organoid-T-cell coculture systems. Nat Protoc 2020; 15: 15– 39. 10.1038/s41596-019-0232-9 31853056 PMC7610702 · DOI · Paper page
  38. [51]Nozaki K, Mochizuki W, Matsumoto Y, et al. Co-culture with intestinal epithelial organoids allows efficient expansion and motility analysis of intraepithelial lymphocytes. J Gastroenterol 2016; 51: 206– 13. 10.1007/s00535-016-1170-8 26800996 PMC4771822 · DOI
  39. [52]Tsai S, McOlash L, Palen K, et al. Development of primary human pancreatic cancer organoids, matched stromal and immune cells and 3D tumor microenvironment models. BMC Cancer 2018; 18: 335. 10.1186/s12885-018-4238-4 29587663 PMC5870823 · DOI · Paper page
  40. [54]Cook L, Stahl M, Han X, et al. Suppressive and Gut-Reparative functions of human type 1 T regulatory cells. Gastroenterology 2019; 157: 1584– 98. 10.1053/j.gastro.2019.09.002 31513797 · DOI
  41. [55]Kong JCH, Guerra GR, Millen RM, et al. Tumor-Infiltrating lymphocyte function predicts response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. JCO Precis Oncol 2018; 2: 1– 15. 10.1200/PO.18.00075 35135158 · DOI
  42. [57]Noel G, Baetz NW, Staab JF, et al. A primary human macrophage-enteroid co-culture model to investigate mucosal gut physiology and host-pathogen interactions. Sci Rep 2017; 7: 45270. 10.1038/srep45270 28345602 PMC5366908 · DOI · Paper page
  43. [58]Jarret A, Jackson R, Duizer C, et al. Enteric nervous system-derived IL-18 orchestrates mucosal barrier immunity. Cell 2020; 180: e12: 50– 63. 10.1016/j.cell.2019.12.016 PMC7339937 31923399 · DOI
  44. [59]Engel MA, Leffler A, Niedermirtl F, et al. TRPA1 and substance P mediate colitis in mice. Gastroenterology 2011; 141: 1346– 58. 10.1053/j.gastro.2011.07.002 21763243 · DOI
  45. [60]Drokhlyansky E, Smillie CS, Van Wittenberghe N, et al. The human and mouse enteric nervous system at single-cell resolution. Cell 2020; 182: e23: 1606– 22. 10.1016/j.cell.2020.08.003 PMC8358727 32888429 · DOI
  46. [61]Takahashi T, Fujishima K, Kengaku M. Modeling intestinal stem cell function with organoids. Int J Mol Sci 2021; 22. PMC8535974 34681571
  47. [62]Bellono NW, Bayrer JR, Leitch DB, et al. Enterochromaffin cells are gut Chemosensors that couple to sensory neural pathways. Cell 2017; 170: e16: 185– 98. 10.1016/j.cell.2017.05.034 PMC5839326 28648659 · DOI · Paper page
  48. [63]Workman MJ, Mahe MM, Trisno S, et al. Engineered human pluripotent-stem-cell-derived intestinal tissues with a functional enteric nervous system. Nat Med 2017; 23: 49– 59. 10.1038/nm.4233 27869805 PMC5562951 · DOI
  49. [64]Loffet E, Brossard L, Mahe MM. Pluripotent stem cell derived intestinal organoids with an enteric nervous system. Methods Cell Biol 2020; 159: 175– 99. 10.1016/bs.mcb.2020.04.012 32586442 · DOI
  50. [65]Park CS, Nguyen LP, Yong D. Development of colonic organoids containing enteric nerves or blood vessels from human embryonic stem cells. Cells 2020; 9: 2209. 10.3390/cells9102209 PMC7600593 33003541 · DOI
  51. [66]Eicher AK, Kechele DO, Sundaram N, et al. Functional human gastrointestinal organoids can be engineered from three primary germ layers derived separately from pluripotent stem cells. Cell Stem Cell 2022; 29: 36– 51. 10.1016/j.stem.2021.10.010 34856121 PMC8741755 · DOI
  52. [67]Spadoni I, Zagato E, Bertocchi A, et al. A gut-vascular barrier controls the systemic dissemination of bacteria. Science 2015; 350: 830– 4. 10.1126/science.aad0135 26564856 · DOI
  53. [68]Rafii S, Butler JM, Ding B-S. Angiocrine functions of organ-specific endothelial cells. Nature 2016; 529: 316– 25. 10.1038/nature17040 26791722 PMC4878406 · DOI
  54. [69]Carloni S, Bertocchi A, Mancinelli S, et al. Identification of a choroid plexus vascular barrier closing during intestinal inflammation. Science 2021; 374: 439– 48. 10.1126/science.abc6108 34672740 · DOI
  55. [70]Cromer WE, Mathis JM, Granger DN, et al. Role of the endothelium in inflammatory bowel diseases. World J Gastroenterol 2011; 17: 578– 93. 10.3748/wjg.v17.i5.578 21350707 PMC3040330 · DOI
  56. [72]Takahashi Y, Sekine K, Kin T, et al. Self-Condensation culture enables vascularization of tissue fragments for efficient therapeutic transplantation. Cell Rep 2018; 23: 1620– 9. 10.1016/j.celrep.2018.03.123 29742420 PMC8289710 · DOI
  57. [73]Wimmer RA, Leopoldi A, Aichinger M, et al. Generation of blood vessel organoids from human pluripotent stem cells. Nat Protoc 2019; 14: 3082– 100. 10.1038/s41596-019-0213-z 31554955 · DOI · Paper page
  58. [74]Takebe T, Enomura M, Yoshizawa E, et al. Vascularized and complex organ buds from diverse tissues via mesenchymal cell-driven condensation. Cell Stem Cell 2015; 16: 556– 65. 10.1016/j.stem.2015.03.004 25891906 · DOI
  59. [75]Wörsdörfer P, Dalda N, Kern A, et al. Generation of complex human organoid models including vascular networks by incorporation of mesodermal progenitor cells. Sci Rep 2019; 9: 15663. 10.1038/s41598-019-52204-7 31666641 PMC6821804 · DOI
  60. [76]Holloway EM, Wu JH, Czerwinski M, et al. Differentiation of human intestinal organoids with endogenous vascular endothelial cells. Dev Cell 2020; 54: 516– 28. 10.1016/j.devcel.2020.07.023 32841595 PMC7480827 · DOI
  61. [77]McCarthy N, Kraiczy J, Shivdasani RA. Cellular and molecular architecture of the intestinal stem cell niche. Nat Cell Biol 2020; 22: 1033– 41. 10.1038/s41556-020-0567-z 32884148 · DOI
  62. [79]McMahon JA, Takada S, Zimmerman LB, et al. Noggin-mediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite. Genes Dev 1998; 12: 1438– 52. 10.1101/gad.12.10.1438 9585504 PMC316831 · DOI
  63. [80]McCarthy N, Manieri E, Storm EE, et al. Distinct mesenchymal cell populations generate the essential intestinal BMP signaling gradient. Cell Stem Cell 2020; 26: 391– 402. 10.1016/j.stem.2020.01.008 32084389 PMC7412576 · DOI
  64. [81]Greicius G, Kabiri Z, Sigmundsson K, et al. PDGFRα + pericryptal stromal cells are the critical source of Wnts and RSPO3 for murine intestinal stem cells in vivo. Proc Natl Acad Sci U S A 2018; 115: E3173– 81. 10.1073/pnas.1713510115 29559533 PMC5889626 · DOI · Paper page
  65. [83]Lahar N, Lei NY, Wang J, et al. Intestinal subepithelial myofibroblasts support in vitro and in vivo growth of human small intestinal epithelium. PLoS One 2011; 6: e26898. 10.1371/journal.pone.0026898 22125602 PMC3219641 · DOI
  66. [84]Lei NY, Jabaji Z, Wang J, et al. Intestinal subepithelial myofibroblasts support the growth of intestinal epithelial stem cells. PLoS One 2014; 9: e84651. 10.1371/journal.pone.0084651 24400106 PMC3882257 · DOI
  67. [85]Kabiri Z, Greicius G, Madan B, et al. Stroma provides an intestinal stem cell niche in the absence of epithelial Wnts. Development 2014; 141: 2206– 15. 10.1242/dev.104976 24821987 · DOI
  68. [86]Karpus ON, Westendorp BF, Vermeulen JLM, et al. Colonic CD90+ crypt fibroblasts secrete semaphorins to support epithelial growth. Cell Rep 2019; 26: 3698– 708. 10.1016/j.celrep.2019.02.101 30917322 · DOI
  69. [87]Oszvald Ádám, Szvicsek Z, Sándor GO, et al. Extracellular vesicles transmit epithelial growth factor activity in the intestinal stem cell niche. Stem Cells 2020; 38: 291– 300. 10.1002/stem.3113 31675158 · DOI
  70. [88]Liu J, Li P, Wang L, et al. Cancer-Associated fibroblasts provide a stromal niche for liver cancer organoids that confers trophic effects and therapy resistance. Cell Mol Gastroenterol Hepatol 2021; 11: 407– 31. 10.1016/j.jcmgh.2020.09.003 32932015 PMC7788239 · DOI
  71. [90]Seino T, Kawasaki S, Shimokawa M, et al. Human pancreatic tumor organoids reveal loss of stem cell niche factor dependence during disease progression. Cell Stem Cell 2018; 22: 454– 67. 10.1016/j.stem.2017.12.009 29337182 · DOI · Paper page
  72. [91]Biffi G, Oni TE, Spielman B, et al. Il1-Induced JAK/STAT signaling is antagonized by TGFβ to shape CAF heterogeneity in pancreatic ductal adenocarcinoma. Cancer Discov 2019; 9: 282– 301. 10.1158/2159-8290.CD-18-0710 30366930 PMC6368881 · DOI · Paper page
  73. [92]Bittel M, Reichert P, Sarfati I, et al. Visualizing transfer of microbial biomolecules by outer membrane vesicles in microbe-host-communication in vivo. J Extracell Vesicles 2021; 10: e12159. 10.1002/jev2.12159 34664784 PMC8524437 · DOI
  74. [93]Hickey CA, Kuhn KA, Donermeyer DL, et al. Colitogenic Bacteroides thetaiotaomicron antigens access host immune cells in a Sulfatase-Dependent manner via outer membrane vesicles. Cell Host Microbe 2015; 17: 672– 80. 10.1016/j.chom.2015.04.002 25974305 PMC4432250 · DOI
  75. [94]Rooks MG, Garrett WS. Gut microbiota, metabolites and host immunity. Nat Rev Immunol 2016; 16: 341– 52. 10.1038/nri.2016.42 27231050 PMC5541232 · DOI · Paper page
  76. [95]Kaparakis-Liaskos M, Ferrero RL. Immune modulation by bacterial outer membrane vesicles. Nat Rev Immunol 2015; 15: 375– 87. 10.1038/nri3837 25976515 · DOI
  77. [96]Tilg H, Zmora N, Adolph TE, et al. The intestinal microbiota fuelling metabolic inflammation. Nat Rev Immunol 2020; 20: 40– 54. 10.1038/s41577-019-0198-4 31388093 · DOI · Paper page
  78. [97]Wilke G, Funkhouser-Jones LJ, Wang Y, et al. A Stem-Cell-Derived Platform Enables Complete Cryptosporidium Development In Vitro and Genetic Tractability. Cell Host Microbe 2019; 26: 123– 34. 10.1016/j.chom.2019.05.007 31231046 PMC6617391 · DOI
  79. [99]Abuaita BH, Lawrence A-LE, Berger RP, et al. Comparative transcriptional profiling of the early host response to infection by typhoidal and non-typhoidal Salmonella serovars in human intestinal organoids. PLoS Pathog 2021; 17: e1009987. 10.1371/journal.ppat.1009987 34669717 PMC8570492 · DOI
  80. [100]Holthaus D, Kraft MR, Krug SM, et al. Dissection of barrier dysfunction in Organoid-Derived human intestinal epithelia induced by Giardia duodenalis. Gastroenterology 2022; 162: 844– 58. 10.1053/j.gastro.2021.11.022 34822802 · DOI
  81. [101]Lamers MM, Beumer J, van der Vaart J, et al. SARS-CoV-2 productively infects human gut enterocytes. Science 2020; 369: 50– 4. 10.1126/science.abc1669 32358202 PMC7199907 · DOI · Paper page
  82. [102]Zhou J, Li C, Liu X, et al. Infection of bat and human intestinal organoids by SARS-CoV-2. Nat Med 2020; 26: 1077– 83. 10.1038/s41591-020-0912-6 32405028 · DOI
  83. [103]Guo M, Tao W, Flavell RA, et al. Potential intestinal infection and faecal-oral transmission of SARS-CoV-2. Nat Rev Gastroenterol Hepatol 2021; 18: 269– 83. 10.1038/s41575-021-00416-6 33589829 PMC7883337 · DOI
  84. [104]Pleguezuelos-Manzano C, Puschhof J, Rosendahl Huber A, et al. Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli. Nature 2020; 580: 269– 73. 10.1038/s41586-020-2080-8 32106218 PMC8142898 · DOI · Paper page
  85. [105]Giobbe GG, Bonfante F, Jones BC, et al. SARS-CoV-2 infection and replication in human gastric organoids. Nat Commun 2021; 12: 6610. 10.1038/s41467-021-26762-2 34785679 PMC8595698 · DOI
  86. [106]Hill DR, Spence JR. Gastrointestinal organoids: understanding the molecular basis of the host-microbe interface. Cell Mol Gastroenterol Hepatol 2017; 3: 138– 49. 10.1016/j.jcmgh.2016.11.007 28275681 PMC5331777 · DOI
  87. [107]Liu T-C, Kern JT, Jain U, et al. Western diet induces Paneth cell defects through microbiome alterations and farnesoid X receptor and type I interferon activation. Cell Host Microbe 2021; 29: 988– 1001. 10.1016/j.chom.2021.04.004 34010595 PMC8192497 · DOI
  88. [108]Sorrentino G, Perino A, Yildiz E, et al. Bile acids signal via TGR5 to activate intestinal stem cells and epithelial regeneration. Gastroenterology 2020; 159: 956– 68. 10.1053/j.gastro.2020.05.067 32485177 · DOI
  89. [109]Ke X, You K, Pichaud M, et al. Gut bacterial metabolites modulate endoplasmic reticulum stress. Genome Biol 2021; 22: 292. 10.1186/s13059-021-02496-8 34654459 PMC8518294 · DOI
  90. [110]Banerjee A, Herring CA, Chen B, et al. Succinate produced by intestinal microbes promotes specification of tuft cells to suppress ileal inflammation. Gastroenterology 2020; 159: 2101– 15. 10.1053/j.gastro.2020.08.029 32828819 PMC7725941 · DOI
  91. [111]Yin Y-B, de Jonge HR, Wu X, et al. Enteroids for nutritional studies. Mol Nutr Food Res 2019; 63: e1801143. 10.1002/mnfr.201801143 30883003 · DOI
  92. [112]Zang R, Gomez Castro MF, McCune BT, et al. TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes. Sci Immunol 2020; 5. 10.1126/sciimmunol.abc3582. [Epub ahead of print: 13 05 2020]. PMC7285829 32404436 · DOI · Paper page
  93. [113]Heo I, Dutta D, Schaefer DA, et al. Modelling Cryptosporidium infection in human small intestinal and lung organoids. Nat Microbiol 2018; 3: 814– 23. 10.1038/s41564-018-0177-8 29946163 PMC6027984 · DOI
  94. [114]Co JY, Margalef-Català M, Monack DM, et al. Controlling the polarity of human gastrointestinal organoids to investigate epithelial biology and infectious diseases. Nat Protoc 2021; 16: 5171– 92. 10.1038/s41596-021-00607-0 34663962 PMC8841224 · DOI
  95. [115]Co JY, Margalef-Català M, Li X, et al. Controlling epithelial polarity: a human enteroid model for host-pathogen interactions. Cell Rep 2019; 26: 2509– 20. 10.1016/j.celrep.2019.01.108 30811997 PMC6391775 · DOI · Paper page
  96. [116]Salahudeen AA, Choi SS, Rustagi A, et al. Progenitor identification and SARS-CoV-2 infection in human distal lung organoids. Nature 2020; 588: 670– 5. 10.1038/s41586-020-3014-1 33238290 PMC8003326 · DOI · Paper page
  97. [117]Han X, Lee A, Huang S, et al. Lactobacillus rhamnosus GG prevents epithelial barrier dysfunction induced by interferon-gamma and fecal supernatants from irritable bowel syndrome patients in human intestinal enteroids and colonoids. Gut Microbes 2019; 10: 59– 76. 10.1080/19490976.2018.1479625 30040527 PMC6363076 · DOI
  98. [118]Puschhof J, Pleguezuelos-Manzano C, Martinez-Silgado A, et al. Intestinal organoid cocultures with microbes. Nat Protoc 2021; 16: 4633– 49. 10.1038/s41596-021-00589-z 34381208 · DOI
  99. [119]Holokai L, Chakrabarti J, Broda T, et al. Increased programmed Death-Ligand 1 is an early epithelial cell response to Helicobacter pylori infection. PLoS Pathog 2019; 15: e1007468. 10.1371/journal.ppat.1007468 30703170 PMC6380601 · DOI
  100. [120]Williamson IA, Arnold JW, Samsa LA, et al. A high-throughput organoid microinjection platform to study gastrointestinal microbiota and luminal physiology. Cell Mol Gastroenterol Hepatol 2018; 6: 301– 19. 10.1016/j.jcmgh.2018.05.004 30123820 PMC6092482 · DOI
  101. [121]Wang Y, Chiang I-L, Ohara TE, et al. Long-Term culture captures Injury-Repair cycles of colonic stem cells. Cell 2019; 179: e15: 1144– 59. 10.1016/j.cell.2019.10.015 PMC6904908 31708126 · DOI
  102. [122]Wang Y, Kim R, Gunasekara DB, et al. Formation of human colonic crypt array by application of chemical gradients across a shaped epithelial monolayer. Cell Mol Gastroenterol Hepatol 2018; 5: 113– 30. 10.1016/j.jcmgh.2017.10.007 29693040 PMC5904049 · DOI
  103. [123]Wang Y, Gunasekara DB, Reed MI, et al. A microengineered collagen scaffold for generating a polarized crypt-villus architecture of human small intestinal epithelium. Biomaterials 2017; 128: 44– 55. 10.1016/j.biomaterials.2017.03.005 28288348 PMC5392043 · DOI
  104. [125]Fu J, Warmflash A, Lutolf MP. Stem-cell-based embryo models for fundamental research and translation. Nat Mater 2021; 20: 132– 44. 10.1038/s41563-020-00829-9 33199861 PMC7855549 · DOI
  105. [126]Brassard JA, Lutolf MP. Engineering stem cell self-organization to build better organoids. Cell Stem Cell 2019; 24: 860– 76. 10.1016/j.stem.2019.05.005 31173716 · DOI
  106. [127]Nelson CM, Vanduijn MM, Inman JL, et al. Tissue geometry determines sites of mammary branching morphogenesis in organotypic cultures. Science 2006; 314: 298– 300. 10.1126/science.1131000 17038622 PMC2933179 · DOI
  107. [128]Gjorevski N, Nikolaev M, Brown TE, et al. Tissue geometry drives deterministic organoid patterning. Science 2022; 375: eaaw9021. 10.1126/science.aaw9021 34990240 PMC9131435 · DOI · Paper page
  108. [131]Khan S, Tiriac H. Synthetic scaffold for pancreatic organoids. Nat Mater 2022; 21: 9– 11. 10.1038/s41563-021-01177-y 34949871 · DOI
  109. [133]Toda S, Blauch LR, Tang SKY, et al. Programming self-organizing multicellular structures with synthetic cell-cell signaling. Science 2018; 361: 156– 62. 10.1126/science.aat0271 29853554 PMC6492944 · DOI · Paper page
  110. [134]Jalili-Firoozinezhad S, Gazzaniga FS, Calamari EL, et al. A complex human gut microbiome cultured in an anaerobic intestine-on-a-chip. Nat Biomed Eng 2019; 3: 520– 31. 10.1038/s41551-019-0397-0 31086325 PMC6658209 · DOI · Paper page
  111. [135]Schwärzler J, Mayr L, Vich Vila A, et al. PUFA-induced metabolic enteritis as a fuel for Crohn's disease. Gastroenterology 2022; 162: 1690– 704. 10.1053/j.gastro.2022.01.004 35031299 · DOI
  112. [136]Michiba K, Maeda K, Shimomura O, et al. Usefulness of human jejunal spheroid-derived differentiated intestinal epithelial cells for the prediction of intestinal drug absorption in humans. Drug Metab Dispos 2022; 50: 204-213. 10.1124/dmd.121.000796 34992074 · DOI
  113. [137]Yan S, Conley JM, Reilly AM, et al. Intestinal Gpr17 deficiency improves glucose metabolism by promoting GLP-1 secretion. Cell Rep 2022; 38: 110179. 10.1016/j.celrep.2021.110179 34986353 PMC8972502 · DOI
  114. [138]Dedhia PH, Bertaux-Skeirik N, Zavros Y, et al. Organoid Models of Human Gastrointestinal Development and Disease. Gastroenterology 2016; 150: 1098– 112. 10.1053/j.gastro.2015.12.042 26774180 PMC4842135 · DOI
  115. [139]Seidlitz T, Koo B-K, Stange DE. Gastric organoids-an in vitro model system for the study of gastric development and road to personalized medicine. Cell Death Differ 2021; 28: 68– 83. 10.1038/s41418-020-00662-2 33223522 PMC7852679 · DOI
  116. [140]Fujii M, Sato T. Somatic cell-derived organoids as prototypes of human epithelial tissues and diseases. Nat Mater 2021; 20: 156– 69. 10.1038/s41563-020-0754-0 32807924 · DOI
  117. [141]Nanki K, Fujii M, Shimokawa M, et al. Somatic inflammatory gene mutations in human ulcerative colitis epithelium. Nature 2020; 577: 254– 9. 10.1038/s41586-019-1844-5 31853059 · DOI
  118. [142]Kakiuchi N, Yoshida K, Uchino M, et al. Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis. Nature 2020; 577: 260– 5. 10.1038/s41586-019-1856-1 31853061 · DOI
  119. [143]Ringel T, Frey N, Ringnalda F, et al. Genome-Scale CRISPR screening in human intestinal organoids identifies drivers of TGF-β resistance. Cell Stem Cell 2020; 26: 431– 40. 10.1016/j.stem.2020.02.007 32142663 · DOI · Paper page
  120. [144]Bartfeld S, Clevers H. Organoids as model for infectious diseases: culture of human and murine stomach organoids and microinjection of Helicobacter pylori. J Vis Exp 2015. 10.3791/53359. [Epub ahead of print: 12 Nov 2015]. PMC4692704 26650279 · DOI
  121. [145]Bartfeld S, Bayram T, van de Wetering M, et al. In vitro expansion of human gastric epithelial stem cells and their responses to bacterial infection. Gastroenterology 2015; 148: 126– 36. 10.1053/j.gastro.2014.09.042 25307862 PMC4274199 · DOI · Paper page
  122. [146]Schumacher MA, Feng R, Aihara E, et al. Helicobacter pylori-induced sonic hedgehog expression is regulated by NFκB pathway activation: the use of a novel in vitro model to study epithelial response to infection. Helicobacter 2015; 20: 19– 28. 10.1111/hel.12152 25495001 PMC4871133 · DOI
  123. [147]Schlaermann P, Toelle B, Berger H, et al. A novel human gastric primary cell culture system for modelling Helicobacter pylori infection in vitro. Gut 2016; 65: 202– 13. 10.1136/gutjnl-2014-307949 25539675 PMC4752654 · DOI
  124. [149]Lo Y-H, Kolahi KS, Du Y, et al. A CRISPR/Cas9-Engineered ARID1A-Deficient Human Gastric Cancer Organoid Model Reveals Essential and Nonessential Modes of Oncogenic Transformation. Cancer Discov 2021; 11: 1562– 81. 10.1158/2159-8290.CD-20-1109 33451982 PMC8346515 · DOI · Paper page
  125. [151]Rana N, Privitera G, Kondolf HC, et al. GSDMB is increased in IBD and regulates epithelial restitution/repair independent of pyroptosis. Cell 2022; 185: e17: 283– 98. 10.1016/j.cell.2021.12.024 PMC8879997 35021065 · DOI
  126. [152]Günther C, Ruder B, Stolzer I, et al. Interferon lambda promotes Paneth cell death via STAT1 signaling in mice and is increased in inflamed ileal tissues of patients with Crohn's disease. Gastroenterology 2019; 157: e13: 1310– 22. 10.1053/j.gastro.2019.07.031 31352002 · DOI
  127. [153]Xu P, Becker H, Elizalde M, et al. Interleukin-28A induces epithelial barrier dysfunction in CD patient-derived intestinal organoids. Am J Physiol Gastrointest Liver Physiol 2021; 320: G689– 99. 10.1152/ajpgi.00064.2020 33595362 · DOI
  128. [154]Xu P, Elizalde M, Masclee A, et al. Corticosteroid enhances epithelial barrier function in intestinal organoids derived from patients with Crohn's disease. J Mol Med 2021; 99: 805– 15. 10.1007/s00109-021-02045-7 33575854 PMC8164603 · DOI
  129. [156]Krüger J, Groß R, Conzelmann C, et al. Drug inhibition of SARS-CoV-2 replication in human pluripotent stem cell-derived intestinal organoids. Cell Mol Gastroenterol Hepatol 2021; 11: 935– 48. 10.1016/j.jcmgh.2020.11.003 33186749 PMC7655023 · DOI
  130. [157]Ebisudani T, Sugimoto S, Haga K, et al. Direct derivation of human alveolospheres for SARS-CoV-2 infection modeling and drug screening. Cell Rep 2021; 35: 109218. 10.1016/j.celrep.2021.109218 34038715 PMC8133488 · DOI
  131. [159]Son YS, Ki SJ, Thanavel R, et al. Maturation of human intestinal organoids in vitro facilitates colonization by commensal lactobacilli by reinforcing the mucus layer. FASEB J 2020; 34: 9899– 910. 10.1096/fj.202000063R 32602623 · DOI · Paper page
  132. [160]Pradhan S, Weiss AA. Probiotic properties of Escherichia coli Nissle in human intestinal organoids. mBio 2020; 11. 10.1128/mBio.01470-20. [Epub ahead of print: 07 07 2020]. PMC7343996 32636253 · DOI
  133. [162]Cristobal A, van den Toorn HWP, van de Wetering M, et al. 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– 74. 10.1016/j.celrep.2016.12.016 28052255 · DOI
  134. [163]Fujii M, Shimokawa M, Date S, et al. A colorectal tumor organoid library demonstrates progressive loss of niche factor requirements during tumorigenesis. Cell Stem Cell 2016; 18: 827– 38. 10.1016/j.stem.2016.04.003 27212702 · DOI · Paper page
  135. [165]Yan HHN, Siu HC, Ho SL, et al. Organoid cultures of early-onset colorectal cancers reveal distinct and rare genetic profiles. Gut 2020; 69: 2165– 79. 10.1136/gutjnl-2019-320019 32217638 · DOI
  136. [166]Ganesh K, Wu C, O'Rourke KP, et al. A rectal cancer organoid platform to study individual responses to chemoradiation. Nat Med 2019; 25: 1607– 14. 10.1038/s41591-019-0584-2 31591597 PMC7385919 · DOI · Paper page
  137. [167]Yao Y, Xu X, Yang L, et al. Patient-Derived organoids predict chemoradiation responses of locally advanced rectal cancer. Cell Stem Cell 2020; 26: 17– 26. 10.1016/j.stem.2019.10.010 31761724 · DOI · Paper page
  138. [168]Knight JRP, Alexandrou C, Skalka GL, et al. MNK Inhibition Sensitizes KRAS-Mutant Colorectal Cancer to mTORC1 Inhibition by Reducing eIF4E Phosphorylation and c-MYC Expression. Cancer Discov 2021; 11: 1228– 47. 10.1158/2159-8290.CD-20-0652 33328217 PMC7611341 · DOI · Paper page
  139. [169]Buzzelli JN, Ouaret D, Brown G, et al. Colorectal cancer liver metastases organoids retain characteristics of original tumor and acquire chemotherapy resistance. Stem Cell Res 2018; 27: 109– 20. 10.1016/j.scr.2018.01.016 29414601 PMC5842239 · DOI
  140. [170]Ooft SN, Weeber F, Dijkstra KK, et al. Patient-derived organoids can predict response to chemotherapy in metastatic colorectal cancer patients. Sci Transl Med 2019; 11. 10.1126/scitranslmed.aay2574. [Epub ahead of print: 09 10 2019]. 31597751 · DOI · Paper page
  141. [171]Yan HHN, Siu HC, Law S, et al. A comprehensive human gastric cancer organoid Biobank captures tumor subtype heterogeneity and enables therapeutic screening. Cell Stem Cell 2018; 23: e11: 882– 97. 10.1016/j.stem.2018.09.016 30344100 · DOI · Paper page
  142. [172]Steele NG, Chakrabarti J, Wang J, et al. An Organoid-Based preclinical model of human gastric cancer. Cell Mol Gastroenterol Hepatol 2019; 7: 161– 84. 10.1016/j.jcmgh.2018.09.008 30522949 PMC6279812 · DOI
  143. [173]Seidlitz T, Merker SR, Rothe A, et al. Human gastric cancer modelling using organoids. Gut 2019; 68: 207– 17. 10.1136/gutjnl-2017-314549 29703791 PMC6352409 · DOI
  144. [174]Togasaki K, Sugimoto S, Ohta Y, et al. Wnt signaling shapes the histologic variation in diffuse gastric cancer. Gastroenterology 2021; 160: 823– 30. 10.1053/j.gastro.2020.10.047 33217450 · DOI
  145. [175]Gao M, Lin M, Rao M, et al. Development of patient-derived gastric cancer organoids from endoscopic biopsies and surgical tissues. Ann Surg Oncol 2018; 25: 2767– 75. 10.1245/s10434-018-6662-8 30003451 · DOI
  146. [176]Cancer Genome Atlas Research Network, Analysis Working Group: Asan University, BC Cancer Agency, et al. Integrated genomic characterization of oesophageal carcinoma. Nature 2017; 541: 169– 75. 10.1038/nature20805 28052061 PMC5651175 · DOI
  147. [177]Derouet MF, Allen J, Wilson GW, et al. Towards personalized induction therapy for esophageal adenocarcinoma: organoids derived from endoscopic biopsy recapitulate the pre-treatment tumor. Sci Rep 2020; 10: 14514. 10.1038/s41598-020-71589-4 32884042 PMC7471705 · DOI
  148. [179]Zheng B, Ko K-P, Fang X, et al. A new murine esophageal organoid culture method and organoid-based model of esophageal squamous cell neoplasia. iScience 2021; 24: 103440. 10.1016/j.isci.2021.103440 34877497 PMC8633967 · DOI
  149. [180]Hirt CK, Booij TH, Grob L, et al. Drug screening and genome editing in human pancreatic cancer organoids identifies drug-gene interactions and candidates for off-label treatment. Cell Genom 2022; 2: 100095. 10.1016/j.xgen.2022.100095 35187519 PMC7612395 · DOI
  150. [181]Driehuis E, van Hoeck A, Moore K, et al. Pancreatic cancer organoids recapitulate disease and allow personalized drug screening. Proc Natl Acad Sci U S A 2019. 10.1073/pnas.1911273116. [Epub ahead of print: 09 Dec 2019]. PMC6936689 31818951 · DOI
  151. [185]Li L, Knutsdottir H, Hui K, et al. Human primary liver cancer organoids reveal intratumor and interpatient drug response heterogeneity. JCI Insight 2019; 4. 10.1172/jci.insight.121490. [Epub ahead of print: 24 Jan 2019]. PMC6413833 30674722 · DOI
  152. [187]Shi X, Yang J, Liu M, et al. Circular RNA ANAPC7 inhibits tumor growth and muscle wasting via PHLPP2-AKT-TGF-β signaling axis in pancreatic cancer. Gastroenterology 2022; 162: 2004– 17. 10.1053/j.gastro.2022.02.017 35176309 PMC10428768 · DOI
  153. [188]Kato H, Tateishi K, Fujiwara H, et al. MNX1-HNF1B axis is indispensable for intraductal papillary mucinous neoplasm lineages. Gastroenterology 2022; 162: 1272– 87. 10.1053/j.gastro.2021.12.254 34953915 · DOI
  154. [192]Li Z, Ge Y, Dong J, et al. BZW1 facilitates glycolysis and promotes tumor growth in pancreatic ductal adenocarcinoma through potentiating eIF2α phosphorylation. Gastroenterology 2022; 162: 1256– 71. 10.1053/j.gastro.2021.12.249 34951995 PMC9436032 · DOI
  155. [193]Bouchi R, Foo KS, Hua H, et al. FOXO1 inhibition yields functional insulin-producing cells in human gut organoid cultures. Nat Commun 2014; 5: 4242. 10.1038/ncomms5242 24979718 PMC4083475 · DOI
  156. [197]Duluc I, Freund JN, Leberquier C, et al. Fetal endoderm primarily holds the temporal and positional information required for mammalian intestinal development. J Cell Biol 1994; 126: 211– 21. 10.1083/jcb.126.1.211 8027179 PMC2120088 · DOI
  157. [199]Poling HM, Wu D, Brown N, et al. Mechanically induced development and maturation of human intestinal organoids in vivo. Nat Biomed Eng 2018; 2: 429– 42. 10.1038/s41551-018-0243-9 30151330 PMC6108544 · DOI
  158. [200]Sampaziotis F, Justin AW, Tysoe OC, et al. Reconstruction of the mouse extrahepatic biliary tree using primary human extrahepatic cholangiocyte organoids. Nat Med 2017; 23: 954– 63. 10.1038/nm.4360 28671689 · DOI · Paper page
  159. [201]Sampaziotis F, Muraro D, Tysoe OC, et al. Cholangiocyte organoids can repair bile ducts after transplantation in the human liver. Science 2021; 371: 839– 46. 10.1126/science.aaz6964 33602855 PMC7610478 · DOI · Paper page
  160. [202]Fleischer A, Vallejo-Díez S, Martín-Fernández JM, et al. iPSC-Derived intestinal organoids from cystic fibrosis patients acquire CFTR activity upon TALEN-mediated repair of the p.F508del mutation. Mol Ther Methods Clin Dev 2020; 17: 858– 70. 10.1016/j.omtm.2020.04.005 32373648 PMC7195499 · DOI
  161. [203]Miura Y, Li M-Y, Revah O, et al. Engineering brain assembloids to interrogate human neural circuits. Nat Protoc 2022; 17: 15– 35. 10.1038/s41596-021-00632-z 34992269 · DOI
  162. [205]Giobbe GG, Crowley C, Luni C, et al. Extracellular matrix hydrogel derived from decellularized tissues enables endodermal organoid culture. Nat Commun 2019; 10: 5658. 10.1038/s41467-019-13605-4 31827102 PMC6906306 · DOI · Paper page
  163. [206]Giuffrida P, Curti M, Al-Akkad W, et al. Decellularized human gut as a natural 3D platform for research in intestinal fibrosis. Inflamm Bowel Dis 2019; 25: 1740– 50. 10.1093/ibd/izz115 31199863 · DOI
  164. [208]Hunt DR, Klett KC, Mascharak S, et al. Engineered matrices enable the culture of human patient-derived intestinal organoids. Adv Sci 2021; 8: 2004705. 10.1002/advs.202004705 PMC8132048 34026461 · DOI
  165. [209]Curvello R, Alves D, Abud HE, et al. A thermo-responsive collagen-nanocellulose hydrogel for the growth of intestinal organoids. Mater Sci Eng C Mater Biol Appl 2021; 124: 112051. 10.1016/j.msec.2021.112051 33947545 · DOI
  166. [212]Murry CE, Keller G. Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell 2008; 132: 661– 80. 10.1016/j.cell.2008.02.008 18295582 · DOI
  167. [213]Rheinwald JG, Green H. Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells. Cell 1975; 6: 331– 43. 10.1016/S0092-8674(75)80001-8 1052771 · DOI
  168. [214]Kim K-A, Kakitani M, Zhao J, et al. Mitogenic influence of human R-spondin1 on the intestinal epithelium. Science 2005; 309: 1256– 9. 10.1126/science.1112521 16109882 · DOI
  169. [216]Yokota J, Yamashita T, Inui T, et al. Comparison of culture media for human intestinal organoids from the viewpoint of pharmacokinetic studies. Biochem Biophys Res Commun 2021; 566: 115– 22. 10.1016/j.bbrc.2021.06.007 34119823 · DOI
  170. [217]Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. Embryonic stem cell lines derived from human blastocysts. Science 1998; 282: 1145– 7. 10.1126/science.282.5391.1145 9804556 · DOI
  171. [218]Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007; 131: 861– 72. 10.1016/j.cell.2007.11.019 18035408 · DOI · Paper page
  172. [220]Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature 1981; 292: 154– 6. 10.1038/292154a0 7242681 · DOI
  173. [221]Todaro GJ, Green H. Successive transformations of an established cell line by polyoma virus and SV40. Science 1965; 147: 513– 4. 10.1126/science.147.3657.513 14241404 · DOI
  174. [222]Miyoshi H, Stappenbeck TS. In vitro expansion and genetic modification of gastrointestinal stem cells in spheroid culture. Nat Protoc 2013; 8: 2471– 82. 10.1038/nprot.2013.153 24232249 PMC3969856 · DOI
  175. [223]Broda TR, McCracken KW, Wells JM. Generation of human antral and fundic gastric organoids from pluripotent stem cells. Nat Protoc 2019; 14: 28– 50. 10.1038/s41596-018-0080-z 30470820 PMC7951181 · DOI
  176. [224]Pleguezuelos-Manzano C, Puschhof J, van den Brink S, et al. Establishment and culture of human intestinal organoids derived from adult stem cells. Curr Protoc Immunol 2020; 130: e106. 10.1002/cpim.106 32940424 PMC9285512 · DOI
  177. [225]Tysoe OC, Justin AW, Brevini T, et al. Isolation and propagation of primary human cholangiocyte organoids for the generation of bioengineered biliary tissue. Nat Protoc 2019; 14: 1884– 925. 10.1038/s41596-019-0168-0 31110298 · DOI
  178. [226]Driehuis E, Gracanin A, Vries RGJ, et al. Establishment of pancreatic organoids from normal tissue and tumors. STAR Protoc 2020; 1: 100192. 10.1016/j.xpro.2020.100192 33377086 PMC7757566 · DOI
  179. [227]Breunig M, Merkle J, Melzer MK, et al. Differentiation of human pluripotent stem cells into pancreatic duct-like organoids. STAR Protoc 2021; 2: 100913. 10.1016/j.xpro.2021.100913 34917972 PMC8669107 · DOI
  180. [228]Sampaziotis F, de Brito MC, Geti I, et al. Directed differentiation of human induced pluripotent stem cells into functional cholangiocyte-like cells. Nat Protoc 2017; 12: 814– 27. 10.1038/nprot.2017.011 28333915 PMC5467722 · DOI
  181. [229]Driehuis E, Kretzschmar K, Clevers H. Establishment of patient-derived cancer organoids for drug-screening applications. Nat Protoc 2020; 15: 3380– 409. 10.1038/s41596-020-0379-4 32929210 · DOI
  182. [230]Padmanaban V, Grasset EM, Neumann NM, et al. Organotypic culture assays for murine and human primary and metastatic-site tumors. Nat Protoc 2020; 15: 2413– 42. 10.1038/s41596-020-0335-3 32690957 PMC8202162 · DOI
  183. [231]Calandrini C, Drost J. Normal and tumor-derived organoids as a drug screening platform for tumor-specific drug vulnerabilities. STAR Protoc 2022; 3: 101079. 10.1016/j.xpro.2021.101079 35036959 PMC8752949 · DOI
  184. [232]Pascual-Sabater S, Raimondi G, Mato-Berciano A, et al. Preclinical testing of oncolytic adenovirus sensitivity in patient-derived tumor organoids. STAR Protoc 2021; 2: 101017. 10.1016/j.xpro.2021.101017 34950892 PMC8672098 · DOI
  185. [233]Fujii M, Matano M, Nanki K, et al. Efficient genetic engineering of human intestinal organoids using electroporation. Nat Protoc 2015; 10: 1474– 85. 10.1038/nprot.2015.088 26334867 · DOI · Paper page
  186. [234]Roper J, Tammela T, Akkad A, et al. Colonoscopy-based colorectal cancer modeling in mice with CRISPR-Cas9 genome editing and organoid transplantation. Nat Protoc 2018; 13: 217– 34. 10.1038/nprot.2017.136 29300388 PMC6145089 · DOI
  187. [236]Kaltenbacher T, Löprich J, Maresch R, et al. CRISPR somatic genome engineering and cancer modeling in the mouse pancreas and liver. Nat Protoc 2022; 17: 1142– 88. 10.1038/s41596-021-00677-0 35288718 · DOI
  188. [237]van Neerven SM, Ramadan R, van Driel MS, et al. Intestinal organoid co-culture protocol to study cell competition in vitro. STAR Protoc 2022; 3: 101050. 10.1016/j.xpro.2021.101050 34977689 PMC8689363 · DOI
  189. [238]Okamoto T, Natsume Y, Yamanaka H, et al. A protocol for efficient CRISPR-Cas9-mediated knock-in in colorectal cancer patient-derived organoids. STAR Protoc 2021; 2: 100780. 10.1016/j.xpro.2021.100780 34585151 PMC8455475 · DOI
  190. [239]Haga K, Ettayebi K, Tenge VR, et al. Genetic manipulation of human intestinal enteroids demonstrates the necessity of a functional fucosyltransferase 2 gene for Secretor-Dependent human norovirus infection. mBio 2020; 11. 10.1128/mBio.00251-20. [Epub ahead of print: 17 03 2020]. PMC7078471 32184242 · DOI
  191. [240]Lin S-C, Qu L, Ettayebi K, et al. Human norovirus exhibits strain-specific sensitivity to host interferon pathways in human intestinal enteroids. Proc Natl Acad Sci U S A 2020; 117: 23782– 93. 10.1073/pnas.2010834117 32907944 PMC7519316 · DOI
  192. [241]Stroulios G, Stahl M, Elstone F, et al. Culture methods to study Apical-Specific interactions using intestinal organoid models. J Vis Exp 2021. 10.3791/62330. [Epub ahead of print: 23 03 2021]. 33843928 · DOI
  193. [242]Zhang J, Hernandez-Gordillo V, Trapecar M, et al. Coculture of primary human colon monolayer with human gut bacteria. Nat Protoc 2021; 16: 3874– 900. 10.1038/s41596-021-00562-w 34183870 PMC9109719 · DOI
  194. [243]Sayed IM, Tindle C, Fonseca AG, et al. Functional assays with human patient-derived enteroid monolayers to assess the human gut barrier. STAR Protoc 2021; 2: 100680. 10.1016/j.xpro.2021.100680 34337445 PMC8313751 · DOI
  195. [244]Lai BFL, Lu RXZ, Davenport Huyer L, et al. A well plate-based multiplexed platform for incorporation of organoids into an organ-on-a-chip system with a perfusable vasculature. Nat Protoc 2021; 16: 2158– 89. 10.1038/s41596-020-00490-1 33790475 · DOI
  196. [245]Shin W, Kim HJ. 3D in vitro morphogenesis of human intestinal epithelium in a gut-on-a-chip or a hybrid chip with a cell culture insert. Nat Protoc 2022; 17: 910– 39. 10.1038/s41596-021-00674-3 35110737 PMC9675318 · DOI
  197. [246]Aleman J, Kilic T, Mille LS, et al. Microfluidic integration of regeneratable electrochemical affinity-based biosensors for continual monitoring of organ-on-a-chip devices. Nat Protoc 2021; 16: 2564– 93. 10.1038/s41596-021-00511-7 33911259 · DOI
  198. [248]Watanabe S, Kobayashi S, Ogasawara N, et al. Transplantation of intestinal organoids into a mouse model of colitis. Nat Protoc 2022; 17: 649– 71. 10.1038/s41596-021-00658-3 35110738 · DOI
  199. [249]Fumagalli A, Suijkerbuijk SJE, Begthel H, et al. A surgical orthotopic organoid transplantation approach in mice to visualize and study colorectal cancer progression. Nat Protoc 2018; 13: 235– 47. 10.1038/nprot.2017.137 29300390 · DOI
  200. [250]Kasashima H, Duran A, Cid-Diaz T, et al. Mouse model of colorectal cancer: orthotopic co-implantation of tumor and stroma cells in cecum and rectum. STAR Protoc 2021; 2: 100297. 10.1016/j.xpro.2021.100297 33554135 PMC7843928 · DOI

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Authors
Günther, C., Winner, B., Neurath, M. F., & Stappenbeck, T. S.
Affiliations
  • Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
  • Cleveland Clinic (US)
Corresponding author
Günther, Claudia
Venue
Gut
Publisher
BMJ
Published
2022-05-30
Volume
71
Issue
9
Pages
1892-1908
ISSN
  • 0017-5749 (ISSN-L)
  • 1468-3288
OpenAlex
W4281774657
Cited by
145
References
50
Citations by year
2026: 27 · 2025: 40 · 2024: 47 · 2023: 24 · 2022: 7
FWCI
2.65
Type
journal article
Language
en
Open access
Locations
  • Gut (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • OPUS FAU (Kooperativer Bibliotheksverbund Berlin-Brandenburg (KOBV), on behalf of the Universitätsbibliothek Erlangen-Nürnberg) (submittedVersion, cc-by-nc)
Funders
Deutsche Forschungsgemeinschaft (WI 3567/2-1, TRR241, FOR2886, TRR305, GU 1431/5-1)
Topics
  • Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
Keywords
3D organoids, gastrointestinal diseases, organ-on-a-chip, bioprinting, micro manufacturing, gut-brain axis, gut-liver axis, inter-organ communication, patient-derived models, personalized medicine, regenerative medicine, tissue engineering, disease modeling, clinical translation
MeSH terms
Gastrointestinal Diseases, Humans, Models, Theoretical, Organoids, Reproducibility of Results, Bioprinting

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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