{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T03:04:33Z","timestamp":1777604673668,"version":"3.51.4"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2020,9,28]],"date-time":"2020-09-28T00:00:00Z","timestamp":1601251200000},"content-version":"vor","delay-in-days":27,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2020,9,1]],"date-time":"2020-09-01T00:00:00Z","timestamp":1598918400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2020,9]]},"abstract":"\n Background and Aims<\/jats:title>\n In cholestatic liver diseases, ductular reactive (DR) cells extend into the hepatic parenchyma and promote inflammation and fibrosis. We have previously observed that multidrug\u2010resistant 2 (Mdr2\u2212\/\u2212\n <\/jats:italic>) double knockout (DKO) mice lacking tumor necrosis factor\u2013related apoptosis\u2010inducing ligand receptor (Tr\u2212\/\u2212\n <\/jats:italic>) display a more extensive ductular reaction and hepatic fibrosis compared to Mdr2\u2212\/\u2212\n <\/jats:italic> mice. This observation suggests that the magnitude of the DR\u2010cell population may be regulated by apoptosis.<\/jats:p>\n <\/jats:sec>\n \n Approach and Results<\/jats:title>\n To examine this concept, we cultured epithelial cell adhesion molecule\u2013positive reactive cholangioids (ERCs) obtained from wild\u2010type (WT), Tr\u2212\/\u2212\n <\/jats:italic>, Mdr2\u2212\/\u2212\n <\/jats:italic> and DKO mice. Single\u2010cell transcriptomics and immunostaining of both WT and DKO ERCs confirmed their DR\u2010cell phenotype. Moreover, DKO ERCs displayed a unique translational cluster with expression of chemokines, indicating a reactive state. Incubation with the myeloid cell leukemia 1 (MCL1) inhibitor S63845, a proapoptotic BH3\u2010mimetic therapy, significantly decreased DKO and Mdr2\u2212\/\u2212\n <\/jats:italic> ERC viability compared to WT. Intravenous administration of S63845 significantly reduced the DR\u2010cell population and markers of inflammation and liver fibrosis in Mdr2\u2212\/\u2212\n <\/jats:italic> and DKO mice. Furthermore, DKO mice treated with S63845 displayed a significant decrease in hepatic B lymphocytes compared to untreated mice as assessed by high\u2010definition mass cytometry by time\u2010of\u2010flight. Coculture of bone marrow\u2013derived macrophages with ERCs from DKO mouse livers up\u2010regulated expression of the B cell\u2013directed chemokine (C\u2010C motif) ligand 5. Finally, DR cells were noted to be primed for apoptosis with Bcl\u20102 homologous antagonist\/killer activation in vitro<\/jats:italic> and in vivo<\/jats:italic> in primary sclerosing cholangitis liver specimens.<\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n DR cells appear to play a key role in recruiting immune cells to the liver to actively create an inflammatory and profibrogenic microenvironment. Pharmacologic targeting of MCL1 in a mouse model of chronic cholestasis reduces DR\u2010cell and B\u2010cell populations and hepatic fibrosis.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/hep.31211","type":"journal-article","created":{"date-parts":[[2020,3,4]],"date-time":"2020-03-04T07:07:31Z","timestamp":1583305651000},"page":"1013-1028","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":37,"title":["Targeted Apoptosis of Ductular Reactive Cells Reduces Hepatic Fibrosis in a Mouse Model of Cholestasis"],"prefix":"10.1097","volume":"72","author":[{"given":"Adiba I.","family":"Azad","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic,Rochester,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anuradha","family":"Krishnan","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic,Rochester,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leia","family":"Troop","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic,Rochester,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Li","sequence":"additional","affiliation":[{"name":"Biomedical Statistics and Informatics,Mayo Clinic,Rochester,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomohiro","family":"Katsumi","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic,Rochester,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin","family":"Pavelko","sequence":"additional","affiliation":[{"name":"Department of Immunology,Mayo Clinic,Rochester,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enis","family":"Kostallari","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic,Rochester,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Eugenia","family":"Guicciardi","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic,Rochester,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregory J.","family":"Gores","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic,Rochester,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","published-online":{"date-parts":[[2020,9,28]]},"reference":[{"key":"hep31211-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1016\/j.mayocp.2015.03.017","article-title":"The cholangiopathies","volume":"90","year":"2015","journal-title":"Mayo Clin Proc"},{"key":"hep31211-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1056\/NEJMra1506330","article-title":"Primary sclerosing 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