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However, their physiology is poorly understood. By single-cell RNA sequencing, we identified Cd34 and Dpt as hepatic fibroblast\u2013specific genes. Cd34-CreER labeled periportal-venous and periductal fibroblasts, but few pericentral-venous fibroblasts. Cd34+ fibroblasts generated \u223c25% of myofibroblasts in periportal fibrosis and \u223c40% of cancer-associated fibroblasts (CAFs) in intrahepatic cholangiocarcinoma (ICC). Myofibroblast formation by Cd34+ fibroblasts required Tgfbr2. Depletion of Cd34+ fibroblasts increased the frequency of the ductal epithelial cells under homeostasis and accelerated the progression of ICC. Dpt-CreER labeled periportal- and pericentral-venous fibroblasts, but much less periductal fibroblasts. Dpt+ cells generated \u223c15% of myofibroblasts in periportal fibrosis, but few myofibroblasts in pericentral fibrosis or CAFs in ICC. Thus, an orthogonal combination of Cd34-CreER and Dpt-CreER dissected the fates of periductal, periportal-venous, and pericentral-venous fibroblasts. Both periductal and periportal-venous fibroblasts contribute to liver fibrosis. Periductal fibroblasts also contribute to ductal homeostasis and ICC progression.<\/jats:p>","DOI":"10.1084\/jem.20232123","type":"journal-article","created":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T02:20:50Z","timestamp":1736389250000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":10,"title":["Periductal fibroblasts participate in liver homeostasis, fibrosis, and tumorigenesis"],"prefix":"10.1084","volume":"222","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8518-558X","authenticated-orcid":true,"given":"Shan-Shan","family":"Wang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/032x22645","id-type":"ROR","asserted-by":"publisher"}],"name":"Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education 1 Department of Hepatic Oncology, , 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