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In a model for ALGS, <jats:italic>Jag1<\/jats:italic><jats:sup><jats:italic>Ndr\/Ndr<\/jats:italic><\/jats:sup> mice, this occurs with distinct architectural mechanisms in hilar and peripheral IHBDs. Here, we investigated region\u2010specific IHBD characteristics and addressed whether IGF1, a cholangiocyte mitogen that is downregulated in ALGS and in <jats:italic>Jag1<\/jats:italic><jats:sup><jats:italic>Ndr\/Ndr<\/jats:italic><\/jats:sup> mice, can improve biliary outcomes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Intrahepatic cholangiocyte organoids (ICOs) were derived from hilar and peripheral adult <jats:italic>Jag1<\/jats:italic><jats:sup><jats:italic>+\/+<\/jats:italic><\/jats:sup> and <jats:italic>Jag1<\/jats:italic><jats:sup><jats:italic>Ndr\/Ndr<\/jats:italic><\/jats:sup> livers (hICOs and pICOs, respectively). ICOs were grown in Matrigel or microwell arrays, and characterized using bulk RNA sequencing, immunofluorescence, and high throughput analyses of nuclear sizes. ICOs were treated with IGF1, followed by analyses of growth, proliferation, and death. CellProfiler and Python scripts were custom written for image analyses. Key results were validated <jats:italic>in\u00a0vivo<\/jats:italic> by immunostaining.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Cell growth assays and transcriptomics demonstrated that <jats:italic>Jag1<\/jats:italic><jats:sup><jats:italic>Ndr\/Ndr<\/jats:italic><\/jats:sup> ICOs were less proliferative than <jats:italic>Jag1<\/jats:italic><jats:sup><jats:italic>+\/+<\/jats:italic><\/jats:sup> ICOs. IGF1 specifically rescued survival and growth of <jats:italic>Jag1<\/jats:italic><jats:sup><jats:italic>Ndr\/Ndr<\/jats:italic><\/jats:sup> pICOs. <jats:italic>Jag1<\/jats:italic><jats:sup><jats:italic>Ndr\/Ndr<\/jats:italic><\/jats:sup> hICOs were the least proliferative, with lower Notch signalling and an enrichment of hepatocyte signatures and IGF uptake\/transport pathways. <jats:italic>In\u00a0vitro<\/jats:italic> (<jats:italic>Jag1<\/jats:italic><jats:sup><jats:italic>Ndr\/Ndr<\/jats:italic><\/jats:sup> hICOs) and <jats:italic>in\u00a0vivo<\/jats:italic> (<jats:italic>Jag1<\/jats:italic><jats:sup><jats:italic>Ndr\/Ndr<\/jats:italic><\/jats:sup> hilar portal tracts) analyses revealed ectopic HNF4a<jats:sup>+<\/jats:sup> hepatocytes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Hilar and peripheral <jats:italic>Jag1<\/jats:italic><jats:sup><jats:italic>Ndr\/Ndr<\/jats:italic><\/jats:sup> ICOs exhibit differences in Notch signalling status, proliferation, and cholangiocyte commitment which may result in cholangiocyte\u2010to\u2010hepatocyte transdifferentiation. While <jats:italic>Jag1<\/jats:italic><jats:sup><jats:italic>Ndr\/Ndr<\/jats:italic><\/jats:sup> pICOs can be rescued by IGF1, hICOs are unresponsive, perhaps due to their hepatocyte\u2010like state and\/or expression of IGF transport components. IGF1 represents a potential therapeutic for peripheral bile ducts.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.15789","type":"journal-article","created":{"date-parts":[[2023,11,28]],"date-time":"2023-11-28T14:06:35Z","timestamp":1701180395000},"page":"541-558","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Spatially segregated defects and <scp>IGF1<\/scp>\u2010responsiveness of hilar and peripheral biliary organoids from a model of Alagille syndrome"],"prefix":"10.1111","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-4246-9925","authenticated-orcid":false,"given":"Afshan","family":"Iqbal","sequence":"first","affiliation":[{"name":"Department of Cell and Molecular Biology Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1410-8808","authenticated-orcid":false,"given":"Noemi","family":"Van\u00a0Hul","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Biology Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6687-630X","authenticated-orcid":false,"given":"Lenka","family":"Belicova","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Biology Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8068-3486","authenticated-orcid":false,"given":"Agustin A.","family":"Corbat","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Biology Karolinska Institutet  Stockholm 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