Hepatic fibroblasts comprise groups of stromal cells in the liver that are phenotypically distinct from hepatic stellate cells. However, their physiology is poorly understood. By single-cell RNA sequencing, we identified Cd34 and Dpt as hepatic fibroblast–specific genes. Cd34-CreER labeled periportal-venous and periductal fibroblasts, but few pericentral-venous fibroblasts. Cd34+ fibroblasts generated ∼25% of myofibroblasts in periportal fibrosis and ∼40% 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 ∼15% 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.
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January 31 2025
Periductal fibroblasts participate in liver homeostasis, fibrosis, and tumorigenesis
Shan-Shan Wang
,
Shan-Shan Wang
*
(Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing)
1Department of Hepatic Oncology,
Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education
, Shanghai, China
Shan-Shan Wang: [email protected]
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Jia Yuan
,
Jia Yuan
*
(Data curation, Formal analysis, Investigation, Validation, Writing - original draft)
1Department of Hepatic Oncology,
Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education
, Shanghai, China
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Xinyu Thomas Tang
,
Xinyu Thomas Tang
(Data curation, Formal analysis)
2Key Laboratory of Multi-Cell System,
Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences
, Shanghai, China
3
University of Chinese Academy of Sciences
, Beijing, China
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Xiujuan Yin
,
Xiujuan Yin
(Formal analysis, Validation)
2Key Laboratory of Multi-Cell System,
Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences
, Shanghai, China
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Ke Fang
,
Ke Fang
(Data curation, Investigation)
2Key Laboratory of Multi-Cell System,
Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences
, Shanghai, China
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Lin Veronica Chen
,
Lin Veronica Chen
(Formal analysis, Investigation)
2Key Laboratory of Multi-Cell System,
Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences
, Shanghai, China
3
University of Chinese Academy of Sciences
, Beijing, China
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Zhenggang Ren
,
1Department of Hepatic Oncology,
Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education
, Shanghai, China
Zhenggang Ren: [email protected]
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Bo O. Zhou
(Conceptualization, Funding acquisition, Supervision, Writing - original draft, Writing - review & editing)
2Key Laboratory of Multi-Cell System,
Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences
, Shanghai, China
3
University of Chinese Academy of Sciences
, Beijing, China
4State Key Laboratory of Experimental Hematology, Haihe Laboratory of Cell Ecosystem,
Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
, Tianjin, China
Correspondence to Bo O. Zhou: [email protected]
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Shan-Shan Wang
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
*
1Department of Hepatic Oncology,
Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education
, Shanghai, China
Jia Yuan
Data curation, Formal analysis, Investigation, Validation, Writing - original draft
*
1Department of Hepatic Oncology,
Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education
, Shanghai, China
Xinyu Thomas Tang
Data curation, Formal analysis
2Key Laboratory of Multi-Cell System,
Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences
, Shanghai, China
3
University of Chinese Academy of Sciences
, Beijing, China
Xiujuan Yin
Formal analysis, Validation
2Key Laboratory of Multi-Cell System,
Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences
, Shanghai, China
Ke Fang
Data curation, Investigation
2Key Laboratory of Multi-Cell System,
Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences
, Shanghai, China
Lin Veronica Chen
Formal analysis, Investigation
2Key Laboratory of Multi-Cell System,
Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences
, Shanghai, China
3
University of Chinese Academy of Sciences
, Beijing, China
1Department of Hepatic Oncology,
Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education
, Shanghai, China
Bo O. Zhou
Conceptualization, Funding acquisition, Supervision, Writing - original draft, Writing - review & editing
2Key Laboratory of Multi-Cell System,
Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences
, Shanghai, China
3
University of Chinese Academy of Sciences
, Beijing, China
4State Key Laboratory of Experimental Hematology, Haihe Laboratory of Cell Ecosystem,
Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
, Tianjin, China
Correspondence to Bo O. Zhou: [email protected]
Zhenggang Ren: [email protected]
Shan-Shan Wang: [email protected]
*
S.-S. Wang and J. Yuan contributed equally to this paper.
Disclosures: The authors declare no competing interests exist.
Received:
November 17 2023
Revision Received:
September 20 2024
Accepted:
January 08 2025
Online ISSN: 1540-9538
Print ISSN: 0022-1007
Funding
Funder(s):
National Key Program on Stem Cell and Translational Research
- Award Id(s): 2022YFA1104100
Funder(s):
Chinese Academy of Science
- Award Id(s): XDB0990000
Funder(s):
National Natural Science Foundation of China
- Award Id(s): 32425020,82273292,92368101,32270785
Funder(s):
Shanghai Science and Technology Commission
- Award Id(s): 22XD1424000,22ZR1469000
Funder(s):
Haihe Laboratory of Cell Ecosystem Innovation Fund
- Award Id(s): 22HHXBSS00016
© 2025 Wang et al.
2025
Wang et al.
This article is distributed under the terms as described at https://rupress.org/pages/terms102024/.
J Exp Med (2025) 222 (4): e20232123.
Article history
Received:
November 17 2023
Revision Received:
September 20 2024
Accepted:
January 08 2025
Citation
Shan-Shan Wang, Jia Yuan, Xinyu Thomas Tang, Xiujuan Yin, Ke Fang, Lin Veronica Chen, Zhenggang Ren, Bo O. Zhou; Periductal fibroblasts participate in liver homeostasis, fibrosis, and tumorigenesis. J Exp Med 7 April 2025; 222 (4): e20232123. doi: https://doi.org/10.1084/jem.20232123
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