{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T18:17:09Z","timestamp":1793643429997,"version":"4.5.1"},"reference-count":61,"publisher":"American Society for Clinical Investigation","issue":"17","funder":[{"DOI":"10.13039\/100000052","name":"NIH Office of the Director","doi-asserted-by":"crossref","award":["5R01DK09099205"],"award-info":[{"award-number":["5R01DK09099205"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000052","name":"NIH Office of the Director","doi-asserted-by":"crossref","award":["1R01DK10218201A1"],"award-info":[{"award-number":["1R01DK10218201A1"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000052","name":"NIH Office of the Director","doi-asserted-by":"crossref","award":["1R01CA114102"],"award-info":[{"award-number":["1R01CA114102"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,9,7]]},"abstract":"<jats:p>\n                    We developed an in vitro model system where induced pluripotent stem cells (iPSCs) differentiate into 3-dimensional human hepatic organoids (HOs) through stages that resemble human liver during its embryonic development. The HOs consist of hepatocytes, and cholangiocytes, which are organized into epithelia that surround the lumina of bile duct\u2013like structures. The organoids provide a potentially new model for liver regenerative processes, and were used to characterize the effect of different\n                    <jats:italic>JAG1<\/jats:italic>\n                    mutations that cause: (a) Alagille syndrome (ALGS), a genetic disorder where NOTCH signaling pathway mutations impair bile duct formation, which has substantial variability in its associated clinical features; and (b) Tetralogy of Fallot (TOF), which is the most common form of a complex congenital heart disease, and is associated with several different heritable disorders. Our results demonstrate how an iPSC-based organoid system can be used with genome editing technologies to characterize the pathogenetic effect of human genetic disease-causing mutations.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.94954","type":"journal-article","created":{"date-parts":[[2017,9,6]],"date-time":"2017-09-06T17:27:40Z","timestamp":1504718860000},"source":"Crossref","is-referenced-by-count":235,"title":["Human hepatic organoids for the analysis of human genetic diseases"],"prefix":"10.1172","volume":"2","author":[{"given":"Yuan","family":"Guan","sequence":"first","affiliation":[{"name":"Department of Anesthesia,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Anesthesia,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip M.","family":"Garfin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics,"},{"name":"Department of Genetics, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ursula","family":"Ehmer","sequence":"additional","affiliation":[{"name":"Department of Pediatrics,"},{"name":"Department of Genetics, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Hurwitz","sequence":"additional","affiliation":[{"name":"Department of Pediatrics,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greg","family":"Enns","sequence":"additional","affiliation":[{"name":"Department of Pediatrics,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Michie","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stanford University School of Medicine, Stanford, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manhong","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Anesthesia,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Anesthesia,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshihiko","family":"Nishimura","sequence":"additional","affiliation":[{"name":"Department of Anesthesia,"},{"name":"Center for the Advancement of Health and Bioscience, Sunnyvale, California, USA."},{"name":"Central Institute for Experimental Animals, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8928-9968","authenticated-orcid":true,"given":"Julien","family":"Sage","sequence":"additional","affiliation":[{"name":"Department of Pediatrics,"},{"name":"Department of Genetics, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"Peltz","sequence":"additional","affiliation":[{"name":"Department of Anesthesia,"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2017,9,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2318"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0797-235"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/ng0797-243"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2012.01.010"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.40.12.891"},{"key":"B6","first-page":"77","article-title":"Contribution a` l\u2019anatomie pathologique de la maladie bleue (cyanose cardiaque)","volume":"25","author":"Fallot","year":"1881","journal-title":"Marsaille Medical"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510290331"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1017\/S1047951113001686"},{"issue":"1","key":"B9","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1002\/(SICI)1096-8628(19990507)84:1<56::AID-AJMG11>3.0.CO;2-W","article-title":"Jagged1 mutations in patients ascertained with isolated congenital heart defects","volume":"84","author":"Krantz","year":"1999","journal-title":"Am J Med Genet"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1126\/science.7716513"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3272"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/S0962-8924(97)01161-6"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2004.09.004"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1242\/dev.01411"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2013.04.019"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1172\/JCI63065"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1055\/s-2002-34508"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2000.16600"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1242\/dev.052118"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23431"},{"issue":"4","key":"B21","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1242\/dev.129.4.1075","article-title":"A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency","volume":"129","author":"McCright","year":"2002","journal-title":"Development"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/8.5.723"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28024"},{"issue":"3","key":"B24","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1159\/000472362","article-title":"Mapping of microsatellite markers in the Alagille region and screening of microdeletions by genotyping 23 patients","volume":"2","author":"Deleuze","year":"1994","journal-title":"Eur J Hum Genet"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.29.4.233"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1007\/BF00426072"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/1098-1004(2001)17:1<18::AID-HUMU3>3.0.CO;2-T"},{"issue":"1 Pt 3","key":"B28","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.gene.2015.10.065","article-title":"Jagged1 (JAG1): Structure, expression, and disease associations","volume":"576","author":"Grochowski","year":"2016","journal-title":"Gene"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1086\/374386"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2012.153"},{"issue":"1\u20132","key":"B31","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.cell.2014.11.050","article-title":"Long-term culture of genome-stable bipotent stem cells from adult human liver","volume":"160","author":"Huch","year":"2015","journal-title":"Cell"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2012.05.009"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/ng1961"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1242\/dev.016634"},{"key":"B35","first-page":"25","article-title":"The origin of intrahepatic bile duct cells in the mouse","volume":"79","author":"Shiojiri","year":"1984","journal-title":"J Embryol Exp Morphol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.112.198697"},{"key":"B37"},{"key":"B38","first-page":"122","article-title":"Considerations of some architectural properties of the biliary tree and liver in childhood","volume":"14","author":"Landing","year":"1991","journal-title":"Perspect Pediatr Pathol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/ng.722"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2667"},{"key":"B41","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S0070-2153(10)92003-6","article-title":"Canonical and non-canonical Notch ligands","volume":"92","author":"D\u2019Souza","year":"2010","journal-title":"Curr Top Dev Biol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-014-1243-5"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.10208"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2000.18156"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/10.2.163"},{"key":"B46","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms7087","article-title":"Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma","volume":"6","author":"Sia","year":"2015","journal-title":"Nat Commun"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1242\/dev.140731"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1172\/JCI43122"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3294"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3275"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2011.09.022"},{"issue":"3","key":"B52","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1002\/hep.1840020311","article-title":"Arteriohepatic dysplasia in infancy and childhood: a longitudinal study of six patients","volume":"2","author":"Dahms","year":"1982","journal-title":"Hepatology"},{"issue":"1","key":"B53","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1002\/hep.1840030113","article-title":"Arteriohepatic dysplasia. II. Hepatobiliary morphology","volume":"3","author":"Kahn","year":"1983","journal-title":"Hepatology"},{"issue":"4","key":"B54","doi-asserted-by":"crossref","DOI":"10.1053\/j.gastro.2011.06.049","article-title":"Embryonic ductal plate cells give rise to cholangiocytes, periportal hepatocytes, and adult liver progenitor cells","volume":"141","author":"Carpentier","year":"2011","journal-title":"Gastroenterology"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1177\/0192623310374329"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1097\/01.pas.0000161325.36348.25"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2007.070073"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20571"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1172\/JCI78585"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1038\/nature14553"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2016.04.013"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/94954\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T13:35:30Z","timestamp":1779197730000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/94954"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,9,7]]},"references-count":61,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2017,9,7]]},"published-print":{"date-parts":[[2017,9,7]]}},"alternative-id":["10.1172\/jci.insight.94954"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.94954","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,9,7]]},"article-number":"e94954"}}