Perivenous Stellate Cells Are the Main Source of Myofibroblasts and Cancer-Associated Fibroblasts Formed After Chronic Liver Injuries
Corresponding Author
Shan-Shan Wang
Department of Hepatic Oncology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
These authors contributed equally to this work.ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Bo O. Zhou, Ph.D.
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences
320 Yueyang Road
Shanghai 200031, China
E-mail: [email protected]
Tel.: +1-86-21-54921403
or
Shan-Shan Wang, Ph.D.
Department of Hepatic Oncology, Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education
E-mail: [email protected]
Tel.: +1-86-18321396043
or
Zhenggang Ren, M.D., Ph.D.
Department of Hepatic Oncology, Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education
E-mail: [email protected]
Tel.: +1-86-13681971302
Search for more papers by this authorXinyu Thomas Tang
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
University of Chinese Academy of Sciences, Beijing, China
These authors contributed equally to this work.Search for more papers by this authorMinghui Lin
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
These authors contributed equally to this work.Search for more papers by this authorJia Yuan
Department of Hepatic Oncology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
Search for more papers by this authorYi Jacky Peng
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
University of Chinese Academy of Sciences, Beijing, China
Search for more papers by this authorXiujuan Yin
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
Search for more papers by this authorGuoGuo Shang
Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
Search for more papers by this authorGaoxiang Ge
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
Search for more papers by this authorCorresponding Author
Zhenggang Ren
Department of Hepatic Oncology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Bo O. Zhou, Ph.D.
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences
320 Yueyang Road
Shanghai 200031, China
E-mail: [email protected]
Tel.: +1-86-21-54921403
or
Shan-Shan Wang, Ph.D.
Department of Hepatic Oncology, Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education
E-mail: [email protected]
Tel.: +1-86-18321396043
or
Zhenggang Ren, M.D., Ph.D.
Department of Hepatic Oncology, Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education
E-mail: [email protected]
Tel.: +1-86-13681971302
Search for more papers by this authorCorresponding Author
Bo O. Zhou
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Bo O. Zhou, Ph.D.
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences
320 Yueyang Road
Shanghai 200031, China
E-mail: [email protected]
Tel.: +1-86-21-54921403
or
Shan-Shan Wang, Ph.D.
Department of Hepatic Oncology, Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education
E-mail: [email protected]
Tel.: +1-86-18321396043
or
Zhenggang Ren, M.D., Ph.D.
Department of Hepatic Oncology, Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education
E-mail: [email protected]
Tel.: +1-86-13681971302
Search for more papers by this authorCorresponding Author
Shan-Shan Wang
Department of Hepatic Oncology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
These authors contributed equally to this work.ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Bo O. Zhou, Ph.D.
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences
320 Yueyang Road
Shanghai 200031, China
E-mail: [email protected]
Tel.: +1-86-21-54921403
or
Shan-Shan Wang, Ph.D.
Department of Hepatic Oncology, Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education
E-mail: [email protected]
Tel.: +1-86-18321396043
or
Zhenggang Ren, M.D., Ph.D.
Department of Hepatic Oncology, Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education
E-mail: [email protected]
Tel.: +1-86-13681971302
Search for more papers by this authorXinyu Thomas Tang
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
University of Chinese Academy of Sciences, Beijing, China
These authors contributed equally to this work.Search for more papers by this authorMinghui Lin
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
These authors contributed equally to this work.Search for more papers by this authorJia Yuan
Department of Hepatic Oncology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
Search for more papers by this authorYi Jacky Peng
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
University of Chinese Academy of Sciences, Beijing, China
Search for more papers by this authorXiujuan Yin
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
Search for more papers by this authorGuoGuo Shang
Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
Search for more papers by this authorGaoxiang Ge
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
Search for more papers by this authorCorresponding Author
Zhenggang Ren
Department of Hepatic Oncology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Bo O. Zhou, Ph.D.
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences
320 Yueyang Road
Shanghai 200031, China
E-mail: [email protected]
Tel.: +1-86-21-54921403
or
Shan-Shan Wang, Ph.D.
Department of Hepatic Oncology, Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education
E-mail: [email protected]
Tel.: +1-86-18321396043
or
Zhenggang Ren, M.D., Ph.D.
Department of Hepatic Oncology, Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education
E-mail: [email protected]
Tel.: +1-86-13681971302
Search for more papers by this authorCorresponding Author
Bo O. Zhou
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Bo O. Zhou, Ph.D.
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences
320 Yueyang Road
Shanghai 200031, China
E-mail: [email protected]
Tel.: +1-86-21-54921403
or
Shan-Shan Wang, Ph.D.
Department of Hepatic Oncology, Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education
E-mail: [email protected]
Tel.: +1-86-18321396043
or
Zhenggang Ren, M.D., Ph.D.
Department of Hepatic Oncology, Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education
E-mail: [email protected]
Tel.: +1-86-13681971302
Search for more papers by this authorAbstract
Background and Aims
Studies of the identity and pathophysiology of fibrogenic HSCs have been hampered by a lack of genetic tools that permit specific and inducible fate-mapping of these cells in vivo. Here, by single-cell RNA sequencing of nonparenchymal cells from mouse liver, we identified transcription factor 21 (Tcf21) as a unique marker that restricted its expression to quiescent HSCs.
Approach and Results
Tracing Tcf21+ cells by Tcf21-CreER (Cre-Estrogen Receptor fusion protein under the control of Tcf21 gene promoter) targeted ~10% of all HSCs, most of which were located at periportal and pericentral zones. These HSCs were quiescent under steady state but became activated on injuries, generating 62%-67% of all myofibroblasts in fibrotic livers and ~85% of all cancer-associated fibroblasts (CAFs) in liver tumors. Conditional deletion of Transforming Growth Factor Beta Receptor 2 (Tgfbr2) by Tcf21-CreER blocked HSC activation, compromised liver fibrosis, and inhibited liver tumor progression.
Conclusions
In conclusion, Tcf21-CreER–targeted perivenous stellate cells are the main source of myofibroblasts and CAFs in chronically injured livers. TGF-β signaling links HSC activation to liver fibrosis and tumorigenesis.
Supporting Information
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| hep31848-sup-0001-FigS1.tifTIFF image, 1.8 MB | Fig S1 |
| hep31848-sup-0002-FigS2.tifTIFF image, 790.7 KB | Fig S2 |
| hep31848-sup-0003-FigS3.tifTIFF image, 4.5 MB | Fig S3 |
| hep31848-sup-0004-FigS4.tifTIFF image, 12.8 MB | Fig S4 |
| hep31848-sup-0005-FigS5.tifTIFF image, 10.2 MB | Fig S5 |
| hep31848-sup-0006-FigS6.tifTIFF image, 3.1 MB | Fig S6 |
| hep31848-sup-0007-FigS7.tifTIFF image, 8.7 MB | Fig S7 |
| hep31848-sup-0008-FigS8.tifTIFF image, 1.9 MB | Fig S8 |
| hep31848-sup-0009-Supinfo.pdfPDF document, 57.7 KB | Supplementary Material |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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Author names in bold designate shared co-first authorship.
