{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T18:13:27Z","timestamp":1792260807805,"version":"4.4.0"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2021,12,15]],"date-time":"2021-12-15T00:00:00Z","timestamp":1639526400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>Ductular reaction (DR) expands in chronic liver diseases and correlates with disease severity. Besides its potential role in liver regeneration, DR plays a role in the wound\u2010healing response of the liver, promoting periductular fibrosis and inflammatory cell recruitment. However, there is no information regarding its role in intrahepatic angiogenesis. In the current study we investigated the potential contribution of DR cells to hepatic vascular remodeling during chronic liver disease.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>In mouse models of liver injury, DR cells express genes involved in angiogenesis. Among angiogenesis\u2010related genes, the expression of Slit2 and its receptor Roundabout 1 (Robo1) was localized in DR cells and neoangiogenic vessels, respectively. The angiogenic role of the Slit2\u2013Robo1 pathway in chronic liver disease was confirmed in ROBO1\/2<jats:sup>\u2212\/+<\/jats:sup> mice treated with 3,5\u2010diethoxycarbonyl\u20101,4\u2010dihydrocollidine, which displayed reduced intrahepatic neovascular density compared to wild\u2010type mice. However, ROBO1\/2 deficiency did not affect angiogenesis in partial hepatectomy. In patients with advanced alcohol\u2010associated disease, angiogenesis was associated with DR, and up\u2010regulation of SLIT2\u2013ROBO1 correlated with DR and disease severity. In vitro, human liver\u2010derived organoids produced SLIT2 and induced tube formation of endothelial cells.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Overall, our data indicate that DR expansion promotes angiogenesis through the Slit2\u2013Robo1 pathway and recognize DR cells as key players in the liver wound\u2010healing response.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.32140","type":"journal-article","created":{"date-parts":[[2021,9,7]],"date-time":"2021-09-07T04:54:50Z","timestamp":1630990490000},"page":"353-368","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":38,"title":["Ductular reaction promotes intrahepatic angiogenesis through Slit2\u2013Roundabout 1 signaling"],"prefix":"10.1097","volume":"75","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3726-0087","authenticated-orcid":false,"given":"Mar","family":"Coll","sequence":"first","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS),Barcelona,Spain"},{"name":"Medicine Department, Faculty of Medicine,University of Barcelona,Barcelona,Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd),Barcelona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Ari\u00f1o","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS),Barcelona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celia","family":"Mart\u00ednez\u2010S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS),Barcelona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ester","family":"Garcia\u2010Pras","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS),Barcelona,Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd),Barcelona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Gallego","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS),Barcelona,Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd),Barcelona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Moles","sequence":"additional","affiliation":[{"name":"Cell Death and Proliferation,Institute of Biomedical Research of Barcelona,Spanish National Research Council,Barcelona,Spain"},{"name":"Liver Unit, Hospital Cl\u00ednic,Barcelona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Aguilar\u2010Bravo","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS),Barcelona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delia","family":"Blaya","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS),Barcelona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Vallverd\u00fa","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS),Barcelona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Rubio\u2010Tom\u00e1s","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions 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(IDIBAPS),Barcelona,Spain"},{"name":"Medicine Department, Faculty of Medicine,University of Barcelona,Barcelona,Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd),Barcelona,Spain"},{"name":"Liver Unit, Hospital Cl\u00ednic,Barcelona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Fern\u00e1ndez\u2010Vidal","sequence":"additional","affiliation":[{"name":"Cell Compartments and Signaling Group,Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS),Barcelona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Pol","sequence":"additional","affiliation":[{"name":"Cell Compartments and Signaling Group,Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS),Barcelona,Spain"},{"name":"Department of Biomedical Sciences,Faculty of Medicine,University of Barcelona,Barcelona,Spain"},{"name":"Instituci\u00f3 Catalana de 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