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Here, we performed scRNA-seq on Sox9EGFP+ liver epithelium from mice subjected to bile duct ligation (BDL) and sham controls. We identified 4 BEC subpopulations in sham controls, each associated with specific enrichment of a minimal one or two gene biomarker (\u2018metagene\u2019). Metagenes were validated by hybridization chain reaction fluorescence in situ hybridization, which also facilitated spatial analysis of intrahepatic bile ducts. BECs belonging to a given subpopulation were most likely to have neighbors of the same identity, forming homogenous cellular compartments within otherwise heterogeneous ducts. Subpopulation specific differential gene expression (DGE) analysis revealed that BDL decreases transcriptomic heterogeneity among BECs by suppressing subpopulation specific genes. BDL samples also included a proliferative subpopulation not found in controls, which contained populations enriched for three of the four metagenes. All BEC subpopulations were observed in vitro in monolayer cultures, where they clustered spatially with BECs of the same subtype. Together, our data demonstrate that metagene biomarkers facilitate spatial localization of BEC subpopulations in situ, identify subpopulation-specific injury responses and confirm that BEC heterogeneity is preserved in vitro.<\/jats:p>","DOI":"10.1242\/dev.205690","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T07:34:42Z","timestamp":1789976082000},"source":"Crossref","is-referenced-by-count":0,"title":["Multi-gene biomarkers reveal spatial organization and subpopulation-specific damage response in biliary epithelial cells"],"prefix":"10.1242","volume":"153","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1523-3566","authenticated-orcid":false,"given":"Kendall G.","family":"Kanakanui","sequence":"first","affiliation":[{"name":"Emory University 1 Graduate Program in Genetics and Molecular Biology , , Atlanta, GA 30322,","place":["USA"]},{"name":"University of North Carolina at Chapel Hill 2 Department of Cell Biology & Physiology , , Chapel Hill, NC 27599,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3504-2916","authenticated-orcid":false,"given":"Fransky","family":"Hantelys","sequence":"additional","affiliation":[{"name":"Emory University 3 Department of Medicine, Division of Digestive Diseases , , Atlanta, GA 30322,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3686-2492","authenticated-orcid":false,"given":"Hannah R.","family":"Hrncir","sequence":"additional","affiliation":[{"name":"Emory University 3 Department of Medicine, Division of Digestive Diseases , , Atlanta, GA 30322,","place":["USA"]},{"name":"Emory University 4 Graduate Program in Biochemistry, Cell and Developmental Biology , , Atlanta, GA 30322,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8333-932X","authenticated-orcid":false,"given":"Sergei","family":"Bombin","sequence":"additional","affiliation":[{"name":"Emory University 3 Department of Medicine, Division of Digestive Diseases , , Atlanta, GA 30322,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1298-568X","authenticated-orcid":false,"given":"Adam D.","family":"Gracz","sequence":"additional","affiliation":[{"name":"University of North Carolina at Chapel Hill 2 Department of Cell Biology & Physiology , , Chapel Hill, NC 27599,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2026,10,9]]},"reference":[{"key":"2026101205114853500_DEV205690C1","doi-asserted-by":"publisher","first-page":"R40","DOI":"10.1093\/hmg\/ddy100","article-title":"Cell type discovery using single-cell transcriptomics: implications for ontological representation","volume":"27","author":"Aevermann","year":"2018","journal-title":"Hum. 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