{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T03:04:08Z","timestamp":1783393448518,"version":"3.54.6"},"reference-count":41,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T00:00:00Z","timestamp":1757462400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["SNF; 310030_182679"],"award-info":[{"award-number":["SNF; 310030_182679"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>Cholangiopathies, including primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), and post\u2010COVID\u201019 cholangiopathy (PCC), involve chronic cholangiocyte injury, senescence, epithelial\u2013stromal crosstalk, and progressive fibrosis. However, effective in\u00a0vitro models to capture these interactions are limited. Here, we present a scaffold\u2010free 3D multilineage spheroid model, composed of hepatocyte\u2010like cells (HepG2), cholangiocytes (H69), and hepatic stellate cells (LX\u20102), designed to recapitulate early fibrogenic responses driven by senescent cholangiocytes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Cholangiocyte senescence was induced via ionising radiation prior to spheroid assembly. Fibrosis progression was assessed by mRNA expression of hepatic stellate cell (HSC) activation markers, immunofluorescence, and Masson's trichrome staining, in both direct HSC co\u2010culture and spheroids. To evaluate therapeutic potential, spheroids were treated with A\u20101331852, a selective Bcl\u2010xL inhibitor known to induce apoptosis in senescent cells in PSC and PBC mouse models Drug efficacy was measured by apoptosis induction, reduction of fibrosis, and modulation of stromal activation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Senescent cholangiocytes induced robust HSC activation and promoted extracellular matrix (ECM) deposition, mimicking early fibrogenesis. Treatment with A\u20101331852 selectively induced apoptosis in senescent cholangiocytes and activated HSCs, leading to a marked reduction in fibrosis, consistent with murine PSC and PBC models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This 3D multilineage spheroid model offers a mechanistically relevant and scalable platform to study cholangiocyte senescence\u2010driven fibrosis. Its applicability to senolytic drug testing supports its use in preclinical screening and translational research across a spectrum of cholangiopathies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/liv.70352","type":"journal-article","created":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T06:46:01Z","timestamp":1757573161000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Development and Validation of a Scaffold\u2010Free Human Multilineage Spheroid Model for Early Stage Cholangiopathies Driven by Cholangiocyte Senescence"],"prefix":"10.1111","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8420-5470","authenticated-orcid":false,"given":"Cheuk\u2010Ting","family":"Wu","sequence":"first","affiliation":[{"name":"Institute of Anatomy, University of Bern  Bern 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