{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T12:05:46Z","timestamp":1775304346667,"version":"3.50.1"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2018,12,11]],"date-time":"2018-12-11T00:00:00Z","timestamp":1544486400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hepatol Commun"],"published-print":{"date-parts":[[2019,2]]},"abstract":"\n Hedgehog (HH) signaling participates in hepatobiliary repair after injury and is activated in patients with cholangiopathies. Cholangiopathies are associated with bile duct (BD) hyperplasia, including expansion of peribiliary glands, the niche for biliary progenitor cells. The inflammation\u2010associated cytokine interleukin (IL)\u201033 is also up\u2010regulated in cholangiopathies, including cholangiocarcinoma. We hypothesized that HH signaling synergizes with IL\u201033 in acute inflammation\u2010induced BD hyperplasia. We measured extrahepatic BD (EHBD) thickness and cell proliferation with and without an IL\u201033 challenge in wild\u2010type mice, mice overexpressing Sonic HH (\n pCMV\u2010Shh<\/jats:italic>\n ), and mice with loss of the HH pathway effector glioma\u2010associated oncogene 1 (\n Gli1lacZ\/lacZ<\/jats:italic>\n ).\n LacZ<\/jats:italic>\n reporter mice were used to map the expression of HH effector genes in mouse EHBDs. An EHBD organoid (BDO) system was developed to study biliary progenitor cells\n in vitro<\/jats:italic>\n . EHBDs from the HH overexpressing\n pCMV\u2010Shh<\/jats:italic>\n mice showed increased epithelial cell proliferation and hyperplasia when challenged with IL\u201033. In\n Gli1lacZ\/lacZ<\/jats:italic>\n mice, we observed a decreased proliferative response to IL\u201033 and decreased expression of\n Il6<\/jats:italic>\n . The HH ligands\n Shh<\/jats:italic>\n and Indian HH (\n Ihh<\/jats:italic>\n ) were expressed in epithelial cells, whereas the transcriptional effectors\n Gli1<\/jats:italic>\n ,\n Gli2<\/jats:italic>\n , and\n Gli3<\/jats:italic>\n and the HH receptor Patched1 (\n Ptch1<\/jats:italic>\n ) were expressed in stromal cells, as assessed by\n in situ<\/jats:italic>\n hybridization and\n lacZ<\/jats:italic>\n reporter mice. Although BDO cells lacked canonical HH signaling, they expressed the IL\u201033 receptor suppression of tumorigenicity 2. Accordingly, IL\u201033 treatment directly induced BDO cell proliferation in a nuclear factor \u03baB\u2010dependent manner.\n Conclusion:<\/jats:italic>\n HH ligand overexpression enhances EHBD epithelial cell proliferation induced by IL\u201033. This proproliferative synergism of HH and IL\u201033 involves crosstalk between HH ligand\u2010producing epithelial cells and HH\u2010responding stromal cells.\n <\/jats:p>","DOI":"10.1002\/hep4.1295","type":"journal-article","created":{"date-parts":[[2018,12,11]],"date-time":"2018-12-11T08:25:46Z","timestamp":1544516746000},"page":"277-292","source":"Crossref","is-referenced-by-count":8,"title":["Hedgehog Signaling Modulates Interleukin\u201033\u2010Dependent Extrahepatic Bile Duct Cell Proliferation in Mice"],"prefix":"10.1097","volume":"3","author":[{"given":"Nataliya","family":"Razumilava","sequence":"first","affiliation":[{"name":"Department of Internal Medicine,University of Michigan,Ann Arbor,MI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junya","family":"Shiota","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine,University of Michigan,Ann Arbor,MI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nureen H.","family":"Mohamad Zaki","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine,University of Michigan,Ann Arbor,MI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ramon","family":"Ocadiz\u2010Ruiz","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine,University of Michigan,Ann Arbor,MI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine M.","family":"Cieslak","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine,University of Michigan,Ann Arbor,MI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kais","family":"Zakharia","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine,University of Michigan,Ann Arbor,MI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin L.","family":"Allen","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology,University of Michigan,Ann Arbor,MI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregory J.","family":"Gores","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine,Mayo Clinic,Rochester,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda C.","family":"Samuelson","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine,University of Michigan,Ann Arbor,MI"},{"name":"Molecular and Integrative Physiology,University of Michigan,Ann Arbor,MI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juanita L.","family":"Merchant","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine,University of Michigan,Ann Arbor,MI"},{"name":"Molecular and Integrative Physiology,University of Michigan,Ann 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