{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:12:48Z","timestamp":1785413568876,"version":"3.56.0"},"posted":{"date-parts":[[2025,4,26]]},"group-title":"Physiology","reference-count":48,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,4,26]],"date-time":"2025-04-26T00:00:00Z","timestamp":1745625600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R01 DK139012"],"award-info":[{"award-number":["R01 DK139012"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R03 DK135893"],"award-info":[{"award-number":["R03 DK135893"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["Michigan Pioneer Postdoctoral Fellowship"],"award-info":[{"award-number":["Michigan Pioneer Postdoctoral Fellowship"]}],"id":[{"id":"https:\/\/ror.org\/00jmfr291","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,4,26]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background &amp; Aims<\/jats:title>\n                  <jats:p>The epidermal growth factor (EGF) receptor family of tyrosine kinases regulates development and homeostasis of digestive organs including the liver and bile ducts. It consists of four receptors, EGF receptor (EGFR) and erythroblastoma oncogene B 2-4 (ERBB2\u20134), and their corresponding ligands. EGF signaling promotes intrahepatic cholangiocyte proliferation, bipotent cell transdifferentiation into cholangiocytes, bile duct branching, and cholangiocarcinoma (CCA) aggressiveness.<\/jats:p>\n                  <jats:p>The EGF family signaling contribution to extrahepatic bile duct (EHBD) regeneration is not well defined. This work is aimed at determining the fundamental role of the EGF signaling network in the biliary proliferative response to EHBD obstruction.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Approach<\/jats:title>\n                  <jats:p>\n                    We used mouse bile duct ligation to model obstructive EHBD injury, and human and mouse EHBD organoids for\n                    <jats:italic>in vitro<\/jats:italic>\n                    studies. We tested activating and inhibitory paradigms with recombinant EGF family ligands and receptor antagonists.\n                  <\/jats:p>\n                  <jats:p>Transcriptomic and immunohistochemistry analyses informed EGF signaling changes and cellular localization at homeostasis and after obstruction.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    At homeostasis, the EHBD expressed EGFR ligands\n                    <jats:italic>Tgfa, Btc, Hb-egf<\/jats:italic>\n                    and\n                    <jats:italic>Nrg4<\/jats:italic>\n                    in cholangiocytes, and\n                    <jats:italic>Egf<\/jats:italic>\n                    in stromal cells.\n                    <jats:italic>Erbb2<\/jats:italic>\n                    and\n                    <jats:italic>Erbb3<\/jats:italic>\n                    were predominant receptors expressed in cholangiocytes and\n                    <jats:italic>Egfr<\/jats:italic>\n                    in stromal cells at baseline. After EHBD obstruction, injury-induced biliary hyperproliferation was associated with increased abundance of\n                    <jats:italic>Areg<\/jats:italic>\n                    ,\n                    <jats:italic>Hb-egf<\/jats:italic>\n                    ,\n                    <jats:italic>Tgf\u03b1<\/jats:italic>\n                    and\n                    <jats:italic>Btc<\/jats:italic>\n                    ligands and\n                    <jats:italic>Egfr<\/jats:italic>\n                    receptor in cholangiocytes with resulting epithelial EGFR activation. In biliary organoids, EGFR ligands induced organoid growth, and inhibition of EGFR, but not ERBB2, dampened cholangiocyte proliferation. Accordingly, EGFR inhibition in mice led to a decrease in the biliary proliferative response after EHBD obstruction.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>The obstruction-induced biliary proliferation is an EGFR-mediated response suggesting context-and receptor-specific EGF signaling network involvement in EHBD regeneration after injury.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.04.22.649788","type":"posted-content","created":{"date-parts":[[2025,4,26]],"date-time":"2025-04-26T12:25:11Z","timestamp":1745670311000},"source":"Crossref","is-referenced-by-count":2,"title":["EGFR activation in cholangiocytes promotes extrahepatic bile duct regeneration after injury"],"prefix":"10.64898","author":[{"given":"Ashley N.","family":"Calder","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuki","family":"Sakaguchi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirabelle","family":"Peter","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Tobias","sequence":"additional","affiliation":[{"name":"Penn Genomics and Sequencing Core, Perelman School of Medicine, University of Pennsylvania, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Frankel","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Michigan, Ann Arbor, MI, USA"},{"name":"Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nataliya","family":"Razumilava","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041205414133000_2025.04.22.649788v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)01701-3"},{"key":"2026041205414133000_2025.04.22.649788v1.2","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2010.090675"},{"key":"2026041205414133000_2025.04.22.649788v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-020-0342-4"},{"key":"2026041205414133000_2025.04.22.649788v1.4","doi-asserted-by":"publisher","DOI":"10.1002\/hep.32334"},{"key":"2026041205414133000_2025.04.22.649788v1.5","doi-asserted-by":"publisher","DOI":"10.1002\/hep.32492"},{"key":"2026041205414133000_2025.04.22.649788v1.6","doi-asserted-by":"crossref","unstructured":"Calder AN , Peter MQ , Tobias JW , Zaki NHM , Keeley TM , Frankel TL , Samuelson LC , et al. 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