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Organoid culture to study epithelial cell differentiation and barrier formation in the colon: bridging the gap between monolayer cell culture and human subject research

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Abstract

Organoid culture provides a powerful technology that can bridge the gap between monolayer cell culture on the one hand and whole animal or human subject research on the other. Tissues from many different organs from multiple species, including human, have already been successfully adapted to organoid growth. While optimal culture conditions have not yet been established for all tissue types, it seems that most tissues will, ultimately, be amenable to this type of culture. The colon is one of the tissues in which organoid culture was first established as a technology and which has been most successfully employed. The ready availability of histologically normal tissue as well as both premalignant and malignant tissue (often from the same individual) makes this possible. While individual tumors are highly variable relative to one another in organoid culture, a high degree of genotypic consistency exists between the tumor tissue and the histologically normal counterpart from a given source. Further, source material and tumor tissue in organoid culture demonstrate a high degree of genotypic consistency. Even after 6–9 mo in continuous culture, drift in the mutational profile has been shown to be minimal. Colon tissue maintained in organoid culture, thus, provides a good surrogate for the tissue of origin—a surrogate, however, that is as amenable to intervention with molecular, pharmacological, and immunological approaches as are more-traditionally studied cell lines.

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References

  • Artegiani B, Clevers H (2018) Use and application of 3D-organoid technology. Hum Mol Genet 27:R99–R107

    Article  CAS  PubMed  Google Scholar 

  • Aslam MN, Bergin I, Naik M, Paruchuri T, Hampton A, Rehman M, Dame MK, Rush H, Varani J (2012) A multimineral natural product from red marine algae reduces colon polyp formation in C57BL/6 mice. Nutr Cancer 64:1020–1028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aslam MN, McClintock SD, Attili D, Pandya S, Rehman H, Nadeem DM et al (2020) Ulcerative colitis-derived colonoid culture: a multi-mineral-approach to improve barrier protein expression. Front Cell Dev Biol 8:577221. https://doi.org/10.3389/fcell.2020.577221

    Article  PubMed  PubMed Central  Google Scholar 

  • Aslam MN, Paruchuri T, Bhagavathula N, Varani J (2010) A mineral-rich red algae extract inhibits polyp formation and inflammation in the gastrointestinal tract of mice on a high-fat diet. Integrative Cancer Therapies 9(1):93–99

    Article  PubMed  Google Scholar 

  • Attili D, McClintock SD, Rizvi AH, Pandya S, Rehman H, Nadeem DM et al (2019) Calcium-induced differentiation in normal human colonoid cultures: Cell-cell / cell-matrix adhesion, barrier formation and tissue integrity. PLoS One 14(4):e0215122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baker LA, Tiriac H, Clevers H, Tuveson DA (2016) Modeling pancreatic cancer with organoids. Trends Cancer 2:176–190

    Article  PubMed  PubMed Central  Google Scholar 

  • Bals R, Beisswenger C, Blouquit S, Chinet T (2004) Isolation and air-liquid interface culture of human large airway and bronchiolar epithelial cells. J Cyst Fibros Suppl 2:49–51

    Article  CAS  Google Scholar 

  • Barker N, Huch M, Kujala P, van de Wetering M, Snippert HJ, van Es JH, Sato T, Stange DE, Begthel H, van den Born M, Danenberg E, van den Brink S, Korving J, Abo A, Peters PJ, Wright N, Poulsom R, Clevers H (2010) Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell 6:25–36

    Article  CAS  PubMed  Google Scholar 

  • Baze A, Parmentier C, Hendriks DFG, Hurrell T, Heyd B, Bachellier P, Schuster C, Ingelman-Sundberg M, Richert L (2018) Three-dimensional spheroid primary human hepatocytes in monoculture and coculture with nonparenchymal cells. Tissue Engineering Part C 24:534–540

    Article  CAS  Google Scholar 

  • Beaty MM, Lee EY, Glauert HP (1993) Influence of dietary calcium and vitamin D on colon epithelial cell proliferation and 1,2-dimethylhydrazine-induced colon carcinogenesis in rats fed high fat diets. J Nutr 123:144–152

    Article  CAS  PubMed  Google Scholar 

  • Bhatia S, Nayed T, Sardana S (2019) Introduction to pharmaceutical biotechnology Chap 2. In: Organ culture. IOP Publishing Ltd, pp 2-1–2-28

  • Bootman MD, Bultynck G (2020) Fundamentals of cellular calcium signaling: a primer. Cold Spring Harb Perspect Biol 12:a038802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Broutier L, Mastrogiovanni G, Verstegen MM, Francies HE, Gavarró LM, Bradshaw CR et al (2017) Human primary liver cancer-derived organoid cultures for disease modeling and drug screening. Nat Med 23:1424–1435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Calderon-Gierszal EL, Prins GS (2015) Directed differentiation of human embryonic stem cells into prostate organoids in vitro and its perturbation by low-dose bisphenol A exposure. PLoS One 10(7):e0133238

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Campbell JJ, Davidenko N, Caffarel MM, Cameron RE, Watson CJ (2011) A multifunctional 3D co-culture system for studies of mammary tissue morphogenesis and stem cell biology. PLoS One 6:e25661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cereijido M, Valdés J, Shoshani L, Contreras RG (1998) Role of tight junctions in establishing and maintaining cell polarity. Annu Rev Physiol 60:161–177

    Article  CAS  PubMed  Google Scholar 

  • Cho E, Smith-Warner SA, Spiegelman D, Beeson WL, van den Brandt PA, Colditz GA, Folsom AR, Fraser GE, Freudenheim JL, Giovannucci E, Goldbohm RA, Graham S, Miller AB, Pietinen P, Potter JD, Rohan TE, Terry P, Toniolo P, Virtanen MJ, Willett WC, Wolk A, Wu K, Yaun SS, Zeleniuch-Jacquotte A, Hunter DJ (2004) Dairy foods, calcium, and colorectal cancer: a pooled analysis of 10 cohort studies. J Natl Cancer Inst 96:1015–1012

    Article  CAS  PubMed  Google Scholar 

  • Clevers H (2016) Modeling development and disease with organoids. Cell 165:1586–1597

    Article  CAS  PubMed  Google Scholar 

  • Cunningham KN, Mills LR, Schuman BM, Mwakyusa DH (1994) Long-term prognosis of well-differentiated adenocarcinoma in endoscopically removed colorectal adenomas. Dig Dis Sci 39:2034–2037

    Article  CAS  PubMed  Google Scholar 

  • Dame MK, Attili D, McClintock SD, Dedhia PH, Ouillette P, Hardt O et al (2018) Identification, isolation and characterization of human LGR5-positive colon adenoma cells. Development 145:6

    Article  CAS  Google Scholar 

  • Dame MK, Jiang Y, Appelman HD, Copley KD, McClintock SD, Aslam MN et al (2014) Human colonic crypts in culture: segregation of immunochemical markers in normal versus adenoma-derived. Lab Investig 94(2):222–234

    Article  CAS  PubMed  Google Scholar 

  • Dame MK, McClintock SD, Attili D, Simon B, Copley K, Finkbeiner S (2015) Establishment and genomic characterization of enteroid cultures from human colon adenomas and adenocarcinomas. Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75.

  • Dutta D, Heo I, Clevers H (2017) Disease modeling in stem cell-derived 3D organoid systems. Trends Mol Med 23:393–410

    Article  CAS  PubMed  Google Scholar 

  • Duval K, Grover H, Han L-H, Mou Y, Pegoraro AF, Fredberg J, Chen Z (2017) Modeling physiological events in 2D vs 3D cell culture. Physiology 32:266–277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dye BR, Hill DR, Ferguson MA, Tsai YH, Nagy MS, Dyal R et al (2015) In vitro generation of human pluripotent stem cell derived lung organoids. Elife 4:e05098

    Article  PubMed Central  Google Scholar 

  • Flood A, Peters U, Chatterjee N, Lacey JV Jr, Schairer C, Schatzkin A (2005) Calcium from diet and supplements is associated with reduced risk of colorectal cancer in a prospective cohort of women. Cancer Epidemiol Biomark Prev 14:126–132

    CAS  Google Scholar 

  • Fugii M, Shimokawa M, Date S, Takano A, Matano M, Nanki K et al (2016) A colorectal tumor organoid library demonstrates progressive loss of niche factor requirements during tumorigenesis. Cell Stem Cell 18:827–838

    Article  CAS  Google Scholar 

  • Gatenby RA, Vincent TL (2003) An evolutionary model of carcinogenesis. Cancer Res 63:6212–6220

    CAS  PubMed  Google Scholar 

  • Gilvarry U, Farrell D, Lynch V, Moriarty M, Dooley M, Law E, Clynes M (1990) Cytological differences between normal and malignant human cell populations in culture. Cancer Res 50:3390–3391

    CAS  PubMed  Google Scholar 

  • Green KJ, Simpson CL (2007) Desmosomes: new perspective on a classic. J Invest Dermatol 127:2499–2515

    Article  CAS  PubMed  Google Scholar 

  • Greicius G, Kabiri Z, Sigmundsson K, Liang C, Bunte R, Singh MK, Virshup DM (2018) 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 115:E3173–E3181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hennings H, Holbrook KA (1983) Calcium regulation of cell-cell contact and differentiation of epidermal cells in culture. An ultrastructural study. Exp Cell Res 143:127–142

    Article  CAS  PubMed  Google Scholar 

  • Howell KJ, Kraiczy J, Nayak KM, Gasparetto M, Ross A, Lee C, Mak TN, Koo BK, Kumar N, Lawley T, Sinha A, Rosenstiel P, Heuschkel R, Stegle O, Zilbauer M (2018) DNA methylation and transcription patterns in intestinal epithelial cells from pediatric patients with inflammatory bowel diseases differentiate disease subtypes and associate with outcome. Gastroenterology 154:585–598

    Article  CAS  PubMed  Google Scholar 

  • Huch M (2015) Building stomach in a dish. Nat Cell Biol 17:966–967

    Article  CAS  PubMed  Google Scholar 

  • Huch M, Bonfanti P, Boj SF, Sato T, Loomans CJ, van de Wetering M et al (2013) Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis. EMBO J 32:2708–2721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hynds RE, Giangreco A (2013) Concise review: the relevance of human stem cell-derived organoid models for epithelial translational medicine. Stem Cells 31:417–422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jin K, Teng L, Shen Y, He K, Xu Z, Li G (2010) Patient-derived human tumor tissue xenografts in immunodeficient mice: a systemic review. Clin Transl Oncol 12:473–480

    Article  PubMed  Google Scholar 

  • Kabiri Z, Greicius G, Madan B, Biechele S, Zhong Z, Zaribafzadeh H, Edison H, Aliyev J, Wu Y, Bunte R, Williams BO, Rossant J, Virshup DM (2014) Stroma provides an intestinal stem cell niche in the absence of epithelial Wnts. Development 141:2206–2215

    Article  CAS  PubMed  Google Scholar 

  • Kaushik G, Ponnusamy MP, Batra SK (2018) Concise review: current status of three-dimensional organoids as preclinical models. Stem Cells 36:1329–1340

    Article  PubMed  PubMed Central  Google Scholar 

  • Kesse E, Boutron-Ruault MC, Norat T, Riboli E, Clavel-Chapelon F, E3N Group (2005) Dietary calcium, phosphorus, vitamin D, dairy products and the risk of colorectal adenoma and cancer among French women of the E3N-EPIC prospective study. Int J Cancer 117:137–144

    Article  CAS  PubMed  Google Scholar 

  • Keum N, Aune D, Greenwood DC, Ju W, Giovannucci EL (2014) Calcium intake and colorectal cancer risk: dose-response meta-analysis of prospective observational studies. Int J Cancer 135:1940–1948

    Article  CAS  PubMed  Google Scholar 

  • Kleinsasser NHK, Juchhoff J, Wallner BC, Bergner A, Harreus UA, Gamarra F et al (2004) The use of mini-organ cultures of human upper aerodigestive tract epithelia in ecogenotoxicology. Mutat Res 561:63–73

    Article  CAS  PubMed  Google Scholar 

  • Koike M, Kodera Y, Itoh Y, Nakayama G, Fujiwara M, Hamajima N, Nakao A (2008) Multivariate analysis of the pathologic features of esophageal squamous cell cancer: tumor budding is a significant independent prognostic factor. Ann Surg Oncol 15:1977–1982

    Article  PubMed  Google Scholar 

  • Kowalczyk AP, Green KJ (2013) Structure, function, and regulation of desmosomes. Prog Mol Biol Transl Sci 116:95–118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koyuncuoglu M, Okyay E, Saatli B, Olgan S, Akin M, Saygili U (2012) Tumor budding and E-cadherin expression in endometrial carcinoma: re they prognostic factors indometrial cancer? Gynecol Oncol 125:208–213

    Article  CAS  PubMed  Google Scholar 

  • Kraiczy J, Nayak KM, Howell KJ, Ross A, Forbester J, Salvestrini C, Mustata R, Perkins S, Andersson-Rolf A, Leenen E, Liebert A, Vallier L, Rosenstiel PC, Stegle O, Dougan G, Heuschkel R, Koo BK, Zilbauer M (2019) DNA methylation defines regional identity of human intestinal epithelial organoids and undergoes dynamic changes during development. Gut 68:49–61

    Article  CAS  PubMed  Google Scholar 

  • Larsson SC, Bergkvist L, Rutegård J, Giovannucci E, Wolk A (2006) Calcium and dairy food intakes are inversely associated with colorectal cancer risk in the Cohort of Swedish Men. Am J Clin Nutr 83:667–673

    Article  CAS  PubMed  Google Scholar 

  • Lee J, Rabbani CC, Gao H, Steinhart M, Woodruff B, Pflum Z et al (2020) Hair-bearing human skin generated entirely from pluripotent stem cells. Nature 582:399–404. https://doi.org/10.1038/s41586-020-2352-3 [Epub ahead of print]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li X, Francies HE, Secrier M, Perner J, Miremadi A, Galeano-Dalmau N et al (2018) Organoid cultures recapitulate esophageal adenocarcinoma heterogeneity providing a model for clonality studies and precision therapeutics. Nat Commun 9:2983

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lin R-Z, Chang H-Y (2008) Recent advances in three-dimensional multicellular spheroid culture for biomedical research. Biotechnol J 3:1172–1184

    Article  CAS  PubMed  Google Scholar 

  • Lindborg BA, Brekke JH, Vegoe AL, Ulrich CB, Haider KT, Subramaniam S, Venhuizen SL, Eide CR, Orchard PJ, Chen W, Wang Q, Pelaez F, Scott CM, Kokkoli E, Keirstead SA, Dutton JR, Tolar J, O'Brien TD (2016) Rapid induction of cerebral organoids from human induced pluripotent stem cells using a chemically defined hydrogel and defined cell culture medium. Stem Cells Transl Med 5:970–979

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lindeboom RG, van Voorthuijsen L, Oost KC, Rodríguez-Colman MJ, Luna-Velez MV, Furlan C et al (2018) Integrative multi-omics analysis of intestinal organoid differentiation. Mol Syst Biol 14:e8227

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mariadason JM, Bordonaro M, Aslam F, Shi L, Kuraguchi M, Velcich A, Augenlicht LH (2001) Down-regulation of beta-catenin TCF signaling is linked to colonic epithelial cell differentiation. Cancer Res 61:3465–3471

    CAS  PubMed  Google Scholar 

  • Martin N, Bernard D (2018) Calcium signaling and cellular senescence. Cell Calcium 70:16–23

    Article  CAS  PubMed  Google Scholar 

  • McClintock SD, Attili D, Dame M, Richter A, Silvestri SS, Berner MM et al (2020) Differentiation of human colon tissue in culture: effects of calcium on trans-epithelial electrical resistance and tissue cohesive properties. PLoS One 15(3):e022058

    Article  CAS  Google Scholar 

  • McClintock SD, Colacino JA, Attili D, Dame MK, Richter A, Reddy AR et al (2018) Calcium-induced differentiation of human colon adenomas in colonoid culture: calcium alone versus calcium with additional trace elements. Cancer Prev Res (Phila) 11:413–414

    Article  CAS  Google Scholar 

  • McCracken KW, Catá EM, Crawford CM, Sinagoga KL, Schumacher M, Rockich BE et al (2014) Modelling human development and disease in pluripotent stem-cell-derived gastric organoids. Nature 516:400–404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miyoshi H, Stappenbeck TS (2013) In vitro expansion and genetic modification of gastrointestinal stem cells in spheroid culture. Nat Protoc 8:2471–2482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morson BC, Whiteway JE, Jones EA, Macrae FA, Williams CB (1984) Histopathology and prognosis of malignant colorectal polyps treated by endoscopic polypectomy. Gut 25:437–444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nakano T, Ando S, Takata N, Kawada M, Muguruma K, Sekiguchi K, el at. (2012) Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell 10:771–785.35

    Article  CAS  PubMed  Google Scholar 

  • Newmark HL, Yang K, Kurihara N, Fan K, Augenlicht LH, Lipkin M (2009) Western-style diet-induced colonic tumors and their modulation by calcium and vitamin D in C57Bl/6 mice: a preclinical model for human sporadic colon cancer. Carcinogenesis 30:88–92

    Article  CAS  PubMed  Google Scholar 

  • Nuciforo S, Fotana I, Matter MS, Terracciano LM, Ng CKY, Heim MH et al (2018) Organoid models of human liver cancers derived from tumor needle biopsies. Cell Rep 24:1363–1376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ogawa J, Pao GM, Shokhidrev MN, Verma IM (2018) Glioblastoma model using human cerebral organoids. Cell Rep 23:1220–1229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ootani A, Li X, Sangiorgi E, Ho QT, Ueno H, Toda S, Sugihara H, Fujimoto K, Weissman IL, Capecchi MR, Kuo CJ (2009) Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche. Nat Med 15:701–706

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park SY, Murphy SP, Wilkens LR, Nomura AM, Henderson BE, Kolonel LN (2007) Calcium and vitamin D intake and risk of colorectal cancer: the Multiethnic Cohort Study. Am J Epidemiol 165:784–793

    Article  PubMed  Google Scholar 

  • Reese DH, Friedman RD, Smith JM, Sporn MB (1976) Organ culture of normal and carcinogen-treated rat bladder. Cancer Res 36:2525–2527

    CAS  PubMed  Google Scholar 

  • Reijnders CMA, van Lier A, Ing SR, Ing DK, Scheper RJ, Gibbs S (2015) Development of a full-thickness human skin equivalent in vitro model derived from TERT-immortalized keratinocytes and fibroblasts. Tissue Eng A 21:2448–2459

    Article  CAS  Google Scholar 

  • Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, van Es JH, Abo A, Kujala P, Peters PJ, Clevers H (2009) Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459:262–265

    Article  CAS  PubMed  Google Scholar 

  • Serra D, Mayr U, Boni A, Lukonin I, Rempfler M, Meylan LC et al (2019) Self-organization and symmetry breaking in intestinal organoid development. Nature 569:66–72

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shaukat A, Scouras N, Schünemann HJ (2005) Role of supplemental calcium in the recurrence of colorectal adenomas: a metaanalysis of randomized controlled trials. Am J Gastroenterol 100:390–394

    Article  CAS  PubMed  Google Scholar 

  • Singh N, Aslam MN, Varani J, Chakrabarty S (2015) Induction of calcium sensing receptor in human colon cancer cells by calcium, vitamin D and aquamin: promotion of a more differentiated, less malignant and indolent phenotype. Mol Carcinog 54:543–553

    Article  CAS  PubMed  Google Scholar 

  • Spence JR, Mayhew CN, Rankin SA, Kuhar MF, Vallance JE, Tolle K, Hoskins EE, Kalinichenko VV, Wells SI, Zorn AM, Shroyer NF, Wells JM (2011) Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature 470:105–109

    Article  PubMed  CAS  Google Scholar 

  • Stewart TA, Yapa KT, Monteith GR (2015) Altered calcium signaling in cancer cells. Biochim Biophys Acta 1848:2502–2511

    Article  CAS  PubMed  Google Scholar 

  • Takasato M, Er PX, Becroft M, Vanslambrouck JM, Stanley EG, Elefanty AG, Little MH (2014) Directing human embryonic stem cell differentiation towards a renal lineage generates a self-organizing kidney. Nat Cell Biol 16:118–126

    Article  CAS  PubMed  Google Scholar 

  • Tammi R, Maibach H (1987) Skin organ culture: why? International J Dermatology 26:150–160

    Article  CAS  Google Scholar 

  • Tavakkol A, Varani J, Elder JT, Zouboulis CC (1999) Maintenance of human skin in organ culture: role for insulin-like growth factor-1 receptor and epidermal growth factor receptor. Arch Dermatol Res 291:643–651

    Article  CAS  PubMed  Google Scholar 

  • Tentler JJ, Tan AC, Weekes CD, Jimeno A, Leong S, Pitts TM, Arcaroli JJ, Messersmith WA, Eckhardt SG (2012) Patient-derived tumour xenografts as models for oncology drug development. Nat Rev Clin Oncol 9:338–350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ueno H, Price AB, Wilkinson KH, Jass JR, Mochizuki H, Talbot IC (2004) A new prognostic staging system for rectal cancer. Ann Surg 240:832–839

    Article  PubMed  PubMed Central  Google Scholar 

  • Van de Wetering M, Francies HE, Francis JM, Bounova G, Lorio F, Pronk A et al (2015) Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 161:933–945

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Varani J (1998) Human skin in organ culture: a model for the study of normal and pathological responses of skin. Histol Histopathol 13:775–783

    CAS  PubMed  Google Scholar 

  • Varani J, Kang S, Stoll S, Elder J (1998) Human psoriatic skin in organ culture: comparison with normal skin exposed to exogenous growth factors and effects of an antibody to the EGF receptor. Pathobiology 66:253–259

    Article  CAS  PubMed  Google Scholar 

  • Varani J, Perone P, Griffiths CE, Inman DR, Fligiel SE, Voorhees JJ (1994) All-trans retinoic acid (RA) stimulates events in organ-cultured human skin that underlie repair. Adult skin from sun-protected and sun-exposed sites responds in an identical manner to RA while neonatal foreskin responds differently. J Clin Invest 94:1747–1756

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Varani J, Perone P, O’Brien-Deming M, Warner RL, Aslam MN, Bhagavathula N, Dame MK, Voorhees JJ (2009) Impaired keratinocyte function on matrix metalloproteinase-1 (MMP-1) damaged collagen. Arch Dermatol Res 301:497–506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Varani J, Perone P, Warner RL, Dame MK, Kang S, Fisher GJ, Voorhees JJ (2008) Vascular tube formation on matrix metalloproteinase-1 - damaged collagen. Brit J Cancer 98:1646–1652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Varani J, Spearman D, Perone P, Fligiel SEG, Datta SC, Wang ZQ, Shao Y, Kang S, Fisher GJ, Voorhees JJ (2001) Inhibition of type I procollagen synthesis by damaged collagen in photoaged skin and by collagenase-degraded collagen in vitro. Amer J Pathol 158:931–942

    Article  CAS  Google Scholar 

  • Varani J, Zeigler ME, Dame MK, Kang S, Fisher GJ, Voorhees JJ, Stoll SW, Elder JT (2001) HB-EGF activation of keratinocyte ErbB receptors mediates epidermal hyperplasia following retinoid treatment: a prominent side effect of retinoid therapy. J Invest Dermatol 117:1335–1341

    Article  CAS  PubMed  Google Scholar 

  • Wang T, Kendig DM, Chang S, Trappanese DM, Chacko S, Moreland RS (2012) Bladder smooth muscle organ culture preparation maintains the contractile phenotype. Am J Physiol Ren Physiol 303:F1382–F1397

    Article  CAS  Google Scholar 

  • Ward NL, Bhagathavula N, Johnston A, Dawes SM, Fu W, Lambert S, Dame MK, Warner RL, Gudjonsson JE, Varani J, Elder JT (2015) Erlotinib-induced skin inflammation is IL-1 mediated in KC-Tie2 mice and human skin organ culture. J Invest Dermatol 135:910–913

    Article  CAS  PubMed  Google Scholar 

  • Weeber F, van de Wetering M, Hoogstraat M, Dijkstra KK, Krijgsman O, Kuilman T et al (2015) Preserved genetic diversity in organoids cultured from biopsies of human colorectal cancer metastases. Proc Natl Acad Sci U S A:112

  • Xiao H, Yoon YS, Hong SM, Roh SA, Cho DH, Yu CS, Kim JC (2013) Poorly differentiated colorectal cancers: correlation of microsatellite instability with clinicopathologic features and survival. Am J Clin Pathol 140:341–347

    Article  PubMed  Google Scholar 

  • Xu B, Yu L, Zhao LZ, Ma DW (2016) Prognostic factors in the patients with T2N0M0 colorectal cancer. World J Surg Oncol 14:76

    Article  PubMed  PubMed Central  Google Scholar 

  • Xue X, Ramakrishnan SK, Weisz K, Triner D, Xie L, Attila D et al (2016) Iron Uptake via DMT1 integrates cell cycle with JAK-STAT3 signaling to promote colorectal tumorigenesis. Cell Metab 24:447–461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang H, Ramakrishnan SK, Triner D, Centofanti B, Maitra D, Győrffy B et al (2015) Tumor-selective proteotoxicity of verteporfin inhibits colon cancer progression independently of YAP1. Sci Signal 6 8:ra98

    Article  CAS  Google Scholar 

  • Zihni C, Mills C, Matter K, Balda MS (2016) Tight junctions: from simple barriers to multifunctional molecular gates. Nat Rev Mol Cell Biol 17:564–580

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported in part by grants CA181855 and CA201782 along with an Administrative Supplement from the Office of Dietary Supplements (National Institutes of Health) to JV.

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  1. The Department of Pathology, The University of Michigan Medical School, Ann Arbor, MI, 48109, USA

    James Varani, Shannon D. McClintock & Muhammad Nadeem Aslam

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  1. James Varani
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  2. Shannon D. McClintock
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Correspondence to James Varani.

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All the authors (JV, SDM, MNA) have declared “no conflict of interest” except grants from National Institutes of Health to JV.

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Varani, J., McClintock, S.D. & Aslam, M.N. Organoid culture to study epithelial cell differentiation and barrier formation in the colon: bridging the gap between monolayer cell culture and human subject research. In Vitro Cell.Dev.Biol.-Animal 57, 174–190 (2021). https://doi.org/10.1007/s11626-020-00534-6

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