{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T10:50:25Z","timestamp":1793875825755,"version":"4.7.0"},"reference-count":20,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2017,11,29]],"date-time":"2017-11-29T00:00:00Z","timestamp":1511913600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2017,11,29]],"date-time":"2017-11-29T00:00:00Z","timestamp":1511913600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2018,1]]},"abstract":"<jats:p>\n                    Cholangiocyte senescence has been linked to primary sclerosing cholangitis (PSC). Persistent secretion of growth factors by senescent cholangiocytes leads to the activation of stromal fibroblasts (ASFs), which are drivers of fibrosis. The activated phenotype of ASFs is characterized by an increased sensitivity to apoptotic stimuli. Here, we examined the mechanisms of apoptotic priming in ASFs and explored a combined targeting strategy to deplete senescent cholangiocytes and ASFs from fibrotic tissue to ameliorate liver fibrosis. Using a coculture system, we determined that senescent cholangiocytes promoted quiescent mesenchymal cell activation in a platelet\u2010derived growth factor (PDGF)\u2010dependent manner. We also identified B\u2010cell lymphoma\u2010extra large (Bcl\u2010xL) as a key survival factor in PDGF\u2010activated human and mouse fibroblasts. Bcl\u2010xL was also up\u2010regulated in senescent cholangiocytes.\n                    <jats:italic toggle=\"yes\">In vitro<\/jats:italic>\n                    , inhibition of Bcl\u2010xL by the small molecule Bcl\u20102 homology domain 3 mimetic, A\u20101331852, or Bcl\u2010xL\u2010specific small interfering RNA induced apoptosis in PDGF\u2010activated fibroblasts, but not in quiescent fibroblasts. Likewise, inhibition of Bcl\u2010xL reduced the survival and increased apoptosis of senescent cholangiocytes, compared to nonsenescent cells. Treatment of multidrug resistance 2 gene knockout (\n                    <jats:italic toggle=\"yes\">Mdr2\u2212\/\u2212<\/jats:italic>\n                    ) mice with A\u20101331852 resulted in an 80% decrease in senescent cholangiocytes, a reduction of fibrosis\u2010inducing growth factors and cytokines, decrease of \u03b1\u2010smooth muscle actin\u2013positive ASFs, and finally in a significant reduction of liver fibrosis.\n                    <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic>\n                    Bcl\u2010xL is a key survival factor in ASFs as well as in senescent cholangiocytes. Treatment with the Bcl\u2010xL\u2010specific inhibitor, A\u20101331852, reduces liver fibrosis, possibly by a dual effect on activated fibroblasts and senescent cholangiocytes. This mechanism represents an attractive therapeutic strategy in biliary fibrosis. (H\n                    <jats:sc>epatology<\/jats:sc>\n                    2018;67:247\u2010259).\n                  <\/jats:p>","DOI":"10.1002\/hep.29464","type":"journal-article","created":{"date-parts":[[2017,8,12]],"date-time":"2017-08-12T11:42:36Z","timestamp":1502538156000},"page":"247-259","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":138,"title":["Targeting senescent cholangiocytes and activated fibroblasts with B\u2010cell lymphoma\u2010extra large inhibitors ameliorates fibrosis in multidrug resistance 2 gene knockout (Mdr2\u2212\/\u2212 ) mice"],"prefix":"10.1097","volume":"67","author":[{"given":"Anja","family":"Moncsek","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology,University Hospital Z\u00fcrich,Z\u00fcrich,Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed S.","family":"Al\u2010Suraih","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology and Center for Cell Signaling in Gastroenterology,Mayo Clinic,Rochester,MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christy E.","family":"Trussoni","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology and Center for Cell Signaling in Gastroenterology,Mayo Clinic,Rochester,MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven P.","family":"O'Hara","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology and Center for Cell Signaling in Gastroenterology,Mayo Clinic,Rochester,MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick L.","family":"Splinter","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology and Center for Cell Signaling in Gastroenterology,Mayo Clinic,Rochester,MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camille","family":"Zuber","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,University Hospital Z\u00fcrich,Z\u00fcrich,Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Patsenker","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,University Hospital Z\u00fcrich,Z\u00fcrich,Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piero V.","family":"Valli","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,University Hospital Z\u00fcrich,Z\u00fcrich,Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian D.","family":"Fingas","sequence":"additional","affiliation":[{"name":"Department of General, Visceral, and Transplantation Surgery,University Hospital Essen,Essen,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Achim","family":"Weber","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Pathology,University Hospital Z\u00fcrich,Z\u00fcrich,Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhu","sequence":"additional","affiliation":[{"name":"The Robert and Arlene Kogod Center on Aging,Mayo Clinic,Rochester,MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamar","family":"Tchkonia","sequence":"additional","affiliation":[{"name":"The Robert and Arlene Kogod Center on Aging,Mayo Clinic,Rochester,MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James L.","family":"Kirkland","sequence":"additional","affiliation":[{"name":"The Robert and Arlene Kogod Center on Aging,Mayo Clinic,Rochester,MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory J.","family":"Gores","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology and Center for Cell Signaling in Gastroenterology,Mayo Clinic,Rochester,MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beat","family":"M\u00fcllhaupt","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,University Hospital Z\u00fcrich,Z\u00fcrich,Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas F.","family":"LaRusso","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology and Center for Cell Signaling in Gastroenterology,Mayo Clinic,Rochester,MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim C.","family":"Mertens","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,University Hospital Z\u00fcrich,Z\u00fcrich,Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2017,11,29]]},"reference":[{"key":"hep29464-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1038\/labinvest.2014.94","article-title":"Characterization of cultured cholangiocytes isolated from livers of patients with primary sclerosing cholangitis","volume":"94","year":"2014","journal-title":"Lab Invest"},{"key":"hep29464-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.1002\/hep.26993","article-title":"Cholangiocyte senescence by way of N\u2010ras activation is a characteristic of primary sclerosing cholangitis","volume":"59","year":"2014","journal-title":"Hepatology"},{"key":"hep29464-bib-0003-20241017","doi-asserted-by":"crossref","first-page":"2247","DOI":"10.1074\/jbc.275.4.2247","article-title":"Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury","volume":"275","year":"2000","journal-title":"J Biol Chem"},{"key":"hep29464-bib-0004-20241017","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1038\/nrc1877","article-title":"Fibroblasts in cancer","volume":"6","year":"2006","journal-title":"Nat Rev Cancer"},{"key":"hep29464-bib-0005-20241017","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1006\/excr.2000.5133","article-title":"Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation","volume":"264","year":"2001","journal-title":"Exp Cell Res"},{"key":"hep29464-bib-0006-20241017","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.diff.2016.07.001","article-title":"The characteristics of activated portal fibroblasts\/myofibroblasts in liver fibrosis","volume":"92","year":"2016","journal-title":"Differentiation"},{"key":"hep29464-bib-0007-20241017","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1158\/0008-5472.CAN-12-2130","article-title":"Therapeutic effects of deleting cancer\u2010associated fibroblasts in cholangiocarcinoma","volume":"73","year":"2013","journal-title":"Cancer Res"},{"key":"hep29464-bib-0008-20241017","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.cell.2012.08.038","article-title":"Relative mitochondrial priming of myeloblasts and normal HSCs determines chemotherapeutic success in AML","volume":"151","year":"2012","journal-title":"Cell"},{"key":"hep29464-bib-0009-20241017","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.molcel.2010.01.025","article-title":"The BCL\u20102 family reunion","volume":"37","year":"2010","journal-title":"Mol Cell"},{"key":"hep29464-bib-0010-20241017","doi-asserted-by":"crossref","first-page":"11190","DOI":"10.1038\/ncomms11190","article-title":"Directed elimination of senescent cells by inhibition of BCL\u2010W and BCL\u2010XL","volume":"7","year":"2016","journal-title":"Nat Commun"},{"key":"hep29464-bib-0011-20241017","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1111\/acel.12445","article-title":"Identification of a novel senolytic agent, navitoclax, targeting the Bcl\u20102 family of anti\u2010apoptotic factors","volume":"15","year":"2016","journal-title":"Aging Cell"},{"key":"hep29464-bib-0012-20241017","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.4161\/cbt.27350","article-title":"Selective anti\u2010cancer agents as anti\u2010aging drugs","volume":"14","year":"2013","journal-title":"Cancer Biol Ther"},{"key":"hep29464-bib-0013-20241017","doi-asserted-by":"crossref","first-page":"71","DOI":"10.3109\/09553002.2014.859763","article-title":"Characterization of DNA damage\u2010induced cellular senescence by ionizing radiation in endothelial cells","volume":"90","year":"2014","journal-title":"Int J Radiat Biol"},{"key":"hep29464-bib-0014-20241017","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1038\/nprot.2010.62","article-title":"Rapid in situ codetection of noncoding RNAs and proteins in cells and formalin\u2010fixed paraffin\u2010embedded tissue sections without protease treatment","volume":"5","year":"2010","journal-title":"Nat Protoc"},{"key":"hep29464-bib-0015-20241017","doi-asserted-by":"crossref","first-page":"22835","DOI":"10.1074\/jbc.M114.563064","article-title":"Platelet\u2010derived growth factor primes cancer\u2010associated fibroblasts for apoptosis","volume":"289","year":"2014","journal-title":"J Biol Chem"},{"key":"hep29464-bib-0016-20241017","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1158\/0008-5472.CAN-08-2724","article-title":"Paracrine signaling by platelet\u2010derived growth factor\u2010CC promotes tumor growth by recruitment of cancer\u2010associated fibroblasts","volume":"69","year":"2009","journal-title":"Cancer Res"},{"key":"hep29464-bib-0017-20241017","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1007\/s00441-016-2467-x","article-title":"Fibroblast activation in cancer: when seed fertilizes soil","volume":"365","year":"2016","journal-title":"Cell Tissue Res"},{"key":"hep29464-bib-0018-20241017","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1159\/000430268","article-title":"Platelet\u2010derived growth factor and transforming growth factor beta1 regulate ARDS\u2010associated lung fibrosis through distinct signaling pathways","volume":"36","year":"2015","journal-title":"Cell Physiol Biochem"},{"key":"hep29464-bib-0019-20241017","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1038\/nm.4010","article-title":"Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice","volume":"22","year":"2016","journal-title":"Nat Med"},{"key":"hep29464-bib-0020-20241017","first-page":"279ra240","article-title":"Exploiting selective BCL\u20102 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy","volume":"7","year":"2015","journal-title":"Sci Transl Med"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.29464","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201801000-00025","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T20:59:05Z","timestamp":1729198745000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201801000-00025"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,11,29]]},"references-count":20,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2018]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.29464","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,11,29]]},"assertion":[{"value":"2017-04-07","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-08-08","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}