{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T07:30:25Z","timestamp":1787729425318,"version":"build-2784847793"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,9,6]],"date-time":"2017-09-06T00:00:00Z","timestamp":1504656000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,9,6]],"date-time":"2017-09-06T00:00:00Z","timestamp":1504656000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The fallopian tube epithelium (FTE) has been recognized as a site of origin of high-grade serous ovarian cancer (HGSC). However, the absence of relevant <jats:italic>in vitro<\/jats:italic> human models that can recapitulate tissue-specific architecture has hindered our understanding of FTE transformation and initiation of HGSC. Here, induced pluripotent stem cells (iPSCs) were used to establish a novel 3-dimensional (3D) human FTE organoid <jats:italic>in vitro<\/jats:italic> model containing the relevant cell types of the human fallopian tube as well as a luminal architecture that closely reflects the organization of fallopian tissues <jats:italic>in vivo<\/jats:italic>. Modulation of Wnt and BMP signaling directed iPSC differentiation into M\u00fcllerian cells and subsequent use of pro-M\u00fcllerian growth factors promoted FTE precursors. The expression and localization of M\u00fcllerian markers verified correct cellular differentiation. An innovative 3D growth platform, which enabled the FTE organoid to self-organize into a convoluted luminal structure, permitted matured differentiation to a FTE lineage. This powerful human-derived FTE organoid model can be used to study the earliest stages of HGSC development and to identify novel and specific biomarkers of early fallopian tube epithelial cell transformation.<\/jats:p>","DOI":"10.1038\/s41598-017-05519-2","type":"journal-article","created":{"date-parts":[[2017,8,31]],"date-time":"2017-08-31T15:57:07Z","timestamp":1504195027000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["Directed Differentiation of Human Induced Pluripotent Stem Cells into Fallopian Tube Epithelium"],"prefix":"10.1038","volume":"7","author":[{"given":"Nur","family":"Yucer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Holzapfel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tilley","family":"Jenkins Vogel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsay","family":"Lenaeus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loren","family":"Ornelas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Laury","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0898-9656","authenticated-orcid":false,"given":"Dhruv","family":"Sareen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Barrett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beth Y.","family":"Karlan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clive N.","family":"Svendsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,9,6]]},"reference":[{"issue":"Suppl 10","key":"5519_CR1","doi-asserted-by":"publisher","first-page":"x16","DOI":"10.1093\/annonc\/mdt463","volume":"24","author":"RJ Kurman","year":"2013","unstructured":"Kurman, R. J. Origin and molecular pathogenesis of ovarian high-grade serous carcinoma. Ann Oncol \n                           24(Suppl 10), x16\u201321, doi:10.1093\/annonc\/mdt463 (2013).","journal-title":"Ann Oncol"},{"key":"5519_CR2","doi-asserted-by":"publisher","first-page":"217","DOI":"10.3389\/fonc.2013.00217","volume":"3","author":"PM Jones","year":"2013","unstructured":"Jones, P. M. & Drapkin, R. Modeling High-Grade Serous Carcinoma: How Converging Insights into Pathogenesis and Genetics are Driving Better Experimental Platforms. Front Oncol \n                           3, 217, doi:10.3389\/fonc.2013.00217 (2013).","journal-title":"Front Oncol"},{"key":"5519_CR3","doi-asserted-by":"publisher","first-page":"5284","DOI":"10.1200\/JCO.2008.18.1107","volume":"26","author":"K Levanon","year":"2008","unstructured":"Levanon, K., Crum, C. & Drapkin, R. New insights into the pathogenesis of serous ovarian cancer and its clinical impact. J Clin Oncol \n                           26, 5284\u20135293, doi:10.1200\/JCO.2008.18.1107 (2008).","journal-title":"J Clin Oncol"},{"key":"5519_CR4","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1016\/j.ygyno.2008.01.012","volume":"109","author":"AK Folkins","year":"2008","unstructured":"Folkins, A. K. et al. A candidate precursor to pelvic serous cancer (p53 signature) and its prevalence in ovaries and fallopian tubes from women with BRCA mutations. Gynecol Oncol \n                           109, 168\u2013173, doi:10.1016\/j.ygyno.2008.01.012 (2008).","journal-title":"Gynecol Oncol"},{"key":"5519_CR5","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1097\/PGP.0b013e318216d447","volume":"30","author":"K Leonhardt","year":"2011","unstructured":"Leonhardt, K., Einenkel, J., Sohr, S., Engeland, K. & Horn, L. C. p53 signature and serous tubal in-situ carcinoma in cases of primary tubal and peritoneal carcinomas and serous borderline tumors of the ovary. Int J Gynecol Pathol \n                           30, 417\u2013424, doi:10.1097\/PGP.0b013e318216d447 (2011).","journal-title":"Int J Gynecol Pathol"},{"key":"5519_CR6","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1097\/01.pas.0000146025.91953.8d","volume":"29","author":"G Singer","year":"2005","unstructured":"Singer, G. et al. Patterns of p53 mutations separate ovarian serous borderline tumors and low- and high-grade carcinomas and provide support for a new model of ovarian carcinogenesis: a mutational analysis with immunohistochemical correlation. Am J Surg Pathol \n                           29, 218\u2013224 (2005).","journal-title":"Am J Surg Pathol"},{"key":"5519_CR7","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1016\/j.ygyno.2014.12.015","volume":"136","author":"SL Eddie","year":"2015","unstructured":"Eddie, S. L. et al. Three-dimensional modeling of the human fallopian tube fimbriae. Gynecol Oncol \n                           136, 348\u2013354, doi:10.1016\/j.ygyno.2014.12.015 (2015).","journal-title":"Gynecol Oncol"},{"key":"5519_CR8","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1186\/1471-2121-14-43","volume":"14","author":"K Lawrenson","year":"2013","unstructured":"Lawrenson, K. et al. In vitro three-dimensional modeling of fallopian tube secretory epithelial cells. BMC Cell Biol \n                           14, 43, doi:10.1186\/1471-2121-14-43 (2013).","journal-title":"BMC Cell Biol"},{"key":"5519_CR9","doi-asserted-by":"publisher","first-page":"1103","DOI":"10.1038\/onc.2009.402","volume":"29","author":"K Levanon","year":"2010","unstructured":"Levanon, K. et al. Primary ex vivo cultures of human fallopian tube epithelium as a model for serous ovarian carcinogenesis. 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Female development in mammals is regulated by Wnt-4 signalling. Nature \n                           397, 405\u2013409, doi:10.1038\/17068 (1999).","DOI":"10.1038\/17068"},{"key":"5519_CR30","doi-asserted-by":"publisher","first-page":"e84881","DOI":"10.1371\/journal.pone.0084881","volume":"9","author":"T Araoka","year":"2014","unstructured":"Araoka, T. et al. Efficient and rapid induction of human iPSCs\/ESCs into nephrogenic intermediate mesoderm using small molecule-based differentiation methods. PLoS One \n                           9, e84881, doi:10.1371\/journal.pone.0084881 (2014).","journal-title":"PLoS One"},{"key":"5519_CR31","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1006\/mcne.2002.1194","volume":"21","author":"K Brannvall","year":"2002","unstructured":"Brannvall, K., Korhonen, L. & Lindholm, D. Estrogen-receptor-dependent regulation of neural stem cell proliferation and differentiation. 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Nat Protoc \n                           6, 1920\u20131928, doi:10.1038\/nprot.2011.410 (2011).","journal-title":"Nat Protoc"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-05519-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-05519-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-05519-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T10:36:18Z","timestamp":1671791778000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-05519-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,9,6]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["5519"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-05519-2","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,9,6]]},"assertion":[{"value":"16 February 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 May 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 September 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests. Intellectual protection-patent pending for iPSC-derive human fallopian tube epithelial organoid protocol has been initiated.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"10741"}}