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ResearchIn-Press PreviewCell biologyHepatology Open Access | 10.1172/JCI199913

TGF-β serves as a critical signaling determinant of liver progenitor cell activation and function

Chenhao Tong,1 Tao Lin,1 Han Wang,2 Luyao Jiang,3 Xiaodong Yuan,4 Wenwu Luo,5 Minghan Zhou,1 Carolina De La Torre,6 Hui Liu,7 Chen Shao,7 Seddik Hammad,1 Hui Gao,8 Jiarong Xie,8 Lei Xu,8 Roman Liebe,9 Zuguang Gu,10 Matthias P. Ebert,11 Huiguo Ding,12 Steven Dooley,1 and Hong-Lei Weng1

1Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

2Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

3Liver Disease Research Laboratory, The First Affiliated Hospital of Ningbo University, Ningbo, China

4Department of General Surgery, The First Affiliated Hospital of USTC, Divis, University of Science and Technology of China, Hefei, China

5Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Anhui, China

6NGS Core Facility, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

7Department of Pathology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, China

8Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo, China

9Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Düsseldorf, Germany

10Institute of Cell and Gene Technology, Shenzhen University of Advanced Technology, Shenzhen, China

11Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

12Department of Gastroenterology and Hepatology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, Germany

Find articles by Tong, C. in: PubMed | Google Scholar

1Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

2Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

3Liver Disease Research Laboratory, The First Affiliated Hospital of Ningbo University, Ningbo, China

4Department of General Surgery, The First Affiliated Hospital of USTC, Divis, University of Science and Technology of China, Hefei, China

5Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Anhui, China

6NGS Core Facility, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

7Department of Pathology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, China

8Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo, China

9Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Düsseldorf, Germany

10Institute of Cell and Gene Technology, Shenzhen University of Advanced Technology, Shenzhen, China

11Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

12Department of Gastroenterology and Hepatology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, Germany

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1Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

2Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

3Liver Disease Research Laboratory, The First Affiliated Hospital of Ningbo University, Ningbo, China

4Department of General Surgery, The First Affiliated Hospital of USTC, Divis, University of Science and Technology of China, Hefei, China

5Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Anhui, China

6NGS Core Facility, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

7Department of Pathology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, China

8Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo, China

9Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Düsseldorf, Germany

10Institute of Cell and Gene Technology, Shenzhen University of Advanced Technology, Shenzhen, China

11Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

12Department of Gastroenterology and Hepatology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, Germany

Find articles by Wang, H. in: PubMed | Google Scholar

1Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

2Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

3Liver Disease Research Laboratory, The First Affiliated Hospital of Ningbo University, Ningbo, China

4Department of General Surgery, The First Affiliated Hospital of USTC, Divis, University of Science and Technology of China, Hefei, China

5Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Anhui, China

6NGS Core Facility, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

7Department of Pathology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, China

8Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo, China

9Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Düsseldorf, Germany

10Institute of Cell and Gene Technology, Shenzhen University of Advanced Technology, Shenzhen, China

11Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

12Department of Gastroenterology and Hepatology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, Germany

Find articles by Jiang, L. in: PubMed | Google Scholar

1Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

2Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

3Liver Disease Research Laboratory, The First Affiliated Hospital of Ningbo University, Ningbo, China

4Department of General Surgery, The First Affiliated Hospital of USTC, Divis, University of Science and Technology of China, Hefei, China

5Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Anhui, China

6NGS Core Facility, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

7Department of Pathology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, China

8Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo, China

9Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Düsseldorf, Germany

10Institute of Cell and Gene Technology, Shenzhen University of Advanced Technology, Shenzhen, China

11Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

12Department of Gastroenterology and Hepatology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, Germany

Find articles by Yuan, X. in: PubMed | Google Scholar

1Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

2Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

3Liver Disease Research Laboratory, The First Affiliated Hospital of Ningbo University, Ningbo, China

4Department of General Surgery, The First Affiliated Hospital of USTC, Divis, University of Science and Technology of China, Hefei, China

5Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Anhui, China

6NGS Core Facility, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

7Department of Pathology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, China

8Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo, China

9Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Düsseldorf, Germany

10Institute of Cell and Gene Technology, Shenzhen University of Advanced Technology, Shenzhen, China

11Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

12Department of Gastroenterology and Hepatology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, Germany

Find articles by Luo, W. in: PubMed | Google Scholar

1Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

2Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

3Liver Disease Research Laboratory, The First Affiliated Hospital of Ningbo University, Ningbo, China

4Department of General Surgery, The First Affiliated Hospital of USTC, Divis, University of Science and Technology of China, Hefei, China

5Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Anhui, China

6NGS Core Facility, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

7Department of Pathology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, China

8Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo, China

9Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Düsseldorf, Germany

10Institute of Cell and Gene Technology, Shenzhen University of Advanced Technology, Shenzhen, China

11Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

12Department of Gastroenterology and Hepatology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, Germany

Find articles by Zhou, M. in: PubMed | Google Scholar

1Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

2Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

3Liver Disease Research Laboratory, The First Affiliated Hospital of Ningbo University, Ningbo, China

4Department of General Surgery, The First Affiliated Hospital of USTC, Divis, University of Science and Technology of China, Hefei, China

5Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Anhui, China

6NGS Core Facility, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

7Department of Pathology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, China

8Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo, China

9Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Düsseldorf, Germany

10Institute of Cell and Gene Technology, Shenzhen University of Advanced Technology, Shenzhen, China

11Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

12Department of Gastroenterology and Hepatology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, Germany

Find articles by De La Torre, C. in: PubMed | Google Scholar |

1Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

2Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

3Liver Disease Research Laboratory, The First Affiliated Hospital of Ningbo University, Ningbo, China

4Department of General Surgery, The First Affiliated Hospital of USTC, Divis, University of Science and Technology of China, Hefei, China

5Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Anhui, China

6NGS Core Facility, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

7Department of Pathology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, China

8Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo, China

9Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Düsseldorf, Germany

10Institute of Cell and Gene Technology, Shenzhen University of Advanced Technology, Shenzhen, China

11Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

12Department of Gastroenterology and Hepatology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, Germany

Find articles by Liu, H. in: PubMed | Google Scholar

1Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

2Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

3Liver Disease Research Laboratory, The First Affiliated Hospital of Ningbo University, Ningbo, China

4Department of General Surgery, The First Affiliated Hospital of USTC, Divis, University of Science and Technology of China, Hefei, China

5Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Anhui, China

6NGS Core Facility, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

7Department of Pathology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, China

8Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo, China

9Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Düsseldorf, Germany

10Institute of Cell and Gene Technology, Shenzhen University of Advanced Technology, Shenzhen, China

11Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

12Department of Gastroenterology and Hepatology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, Germany

Find articles by Shao, C. in: PubMed | Google Scholar

1Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

2Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

3Liver Disease Research Laboratory, The First Affiliated Hospital of Ningbo University, Ningbo, China

4Department of General Surgery, The First Affiliated Hospital of USTC, Divis, University of Science and Technology of China, Hefei, China

5Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Anhui, China

6NGS Core Facility, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

7Department of Pathology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, China

8Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo, China

9Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Düsseldorf, Germany

10Institute of Cell and Gene Technology, Shenzhen University of Advanced Technology, Shenzhen, China

11Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

12Department of Gastroenterology and Hepatology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, Germany

Find articles by Hammad, S. in: PubMed | Google Scholar

1Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

2Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

3Liver Disease Research Laboratory, The First Affiliated Hospital of Ningbo University, Ningbo, China

4Department of General Surgery, The First Affiliated Hospital of USTC, Divis, University of Science and Technology of China, Hefei, China

5Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Anhui, China

6NGS Core Facility, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

7Department of Pathology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, China

8Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo, China

9Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Düsseldorf, Germany

10Institute of Cell and Gene Technology, Shenzhen University of Advanced Technology, Shenzhen, China

11Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

12Department of Gastroenterology and Hepatology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, Germany

Find articles by Gao, H. in: PubMed | Google Scholar

1Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

2Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

3Liver Disease Research Laboratory, The First Affiliated Hospital of Ningbo University, Ningbo, China

4Department of General Surgery, The First Affiliated Hospital of USTC, Divis, University of Science and Technology of China, Hefei, China

5Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Anhui, China

6NGS Core Facility, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

7Department of Pathology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, China

8Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo, China

9Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Düsseldorf, Germany

10Institute of Cell and Gene Technology, Shenzhen University of Advanced Technology, Shenzhen, China

11Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

12Department of Gastroenterology and Hepatology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, Germany

Find articles by Xie, J. in: PubMed | Google Scholar

1Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

2Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

3Liver Disease Research Laboratory, The First Affiliated Hospital of Ningbo University, Ningbo, China

4Department of General Surgery, The First Affiliated Hospital of USTC, Divis, University of Science and Technology of China, Hefei, China

5Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Anhui, China

6NGS Core Facility, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

7Department of Pathology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, China

8Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo, China

9Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Düsseldorf, Germany

10Institute of Cell and Gene Technology, Shenzhen University of Advanced Technology, Shenzhen, China

11Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

12Department of Gastroenterology and Hepatology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, Germany

Find articles by Xu, L. in: PubMed | Google Scholar

1Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

2Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

3Liver Disease Research Laboratory, The First Affiliated Hospital of Ningbo University, Ningbo, China

4Department of General Surgery, The First Affiliated Hospital of USTC, Divis, University of Science and Technology of China, Hefei, China

5Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Anhui, China

6NGS Core Facility, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

7Department of Pathology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, China

8Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo, China

9Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Düsseldorf, Germany

10Institute of Cell and Gene Technology, Shenzhen University of Advanced Technology, Shenzhen, China

11Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

12Department of Gastroenterology and Hepatology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, Germany

Find articles by Liebe, R. in: PubMed | Google Scholar

1Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

2Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

3Liver Disease Research Laboratory, The First Affiliated Hospital of Ningbo University, Ningbo, China

4Department of General Surgery, The First Affiliated Hospital of USTC, Divis, University of Science and Technology of China, Hefei, China

5Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Anhui, China

6NGS Core Facility, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

7Department of Pathology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, China

8Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo, China

9Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Düsseldorf, Germany

10Institute of Cell and Gene Technology, Shenzhen University of Advanced Technology, Shenzhen, China

11Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

12Department of Gastroenterology and Hepatology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, Germany

Find articles by Gu, Z. in: PubMed | Google Scholar

1Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

2Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

3Liver Disease Research Laboratory, The First Affiliated Hospital of Ningbo University, Ningbo, China

4Department of General Surgery, The First Affiliated Hospital of USTC, Divis, University of Science and Technology of China, Hefei, China

5Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Anhui, China

6NGS Core Facility, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

7Department of Pathology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, China

8Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo, China

9Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Düsseldorf, Germany

10Institute of Cell and Gene Technology, Shenzhen University of Advanced Technology, Shenzhen, China

11Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

12Department of Gastroenterology and Hepatology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, Germany

Find articles by Ebert, M. in: PubMed | Google Scholar

1Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

2Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

3Liver Disease Research Laboratory, The First Affiliated Hospital of Ningbo University, Ningbo, China

4Department of General Surgery, The First Affiliated Hospital of USTC, Divis, University of Science and Technology of China, Hefei, China

5Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Anhui, China

6NGS Core Facility, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

7Department of Pathology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, China

8Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo, China

9Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Düsseldorf, Germany

10Institute of Cell and Gene Technology, Shenzhen University of Advanced Technology, Shenzhen, China

11Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

12Department of Gastroenterology and Hepatology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, Germany

Find articles by Ding, H. in: PubMed | Google Scholar |

1Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

2Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

3Liver Disease Research Laboratory, The First Affiliated Hospital of Ningbo University, Ningbo, China

4Department of General Surgery, The First Affiliated Hospital of USTC, Divis, University of Science and Technology of China, Hefei, China

5Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Anhui, China

6NGS Core Facility, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

7Department of Pathology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, China

8Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo, China

9Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Düsseldorf, Germany

10Institute of Cell and Gene Technology, Shenzhen University of Advanced Technology, Shenzhen, China

11Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

12Department of Gastroenterology and Hepatology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, Germany

Find articles by Dooley, S. in: PubMed | Google Scholar

1Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

2Department of Biochemistry, Case Western Reserve University, Cleveland, United States of America

3Liver Disease Research Laboratory, The First Affiliated Hospital of Ningbo University, Ningbo, China

4Department of General Surgery, The First Affiliated Hospital of USTC, Divis, University of Science and Technology of China, Hefei, China

5Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Anhui, China

6NGS Core Facility, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

7Department of Pathology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, China

8Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo, China

9Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Düsseldorf, Germany

10Institute of Cell and Gene Technology, Shenzhen University of Advanced Technology, Shenzhen, China

11Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

12Department of Gastroenterology and Hepatology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, Germany

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Published July 28, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI199913.
Copyright © 2026, Tong et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 28, 2026 - Version history
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Abstract

When massive hepatic necrosis (MHN)-associated acute liver failure (ALF) occurs following severe damage, liver progenitor cells (LPCs) exit quiescence and enter differentiation programs during which they acquire hepatocyte-like functions. To date, how LPCs maintain quiescence under physiological conditions and orchestrate activation following MHN remains largely unknown. Here, we elucidate an essential role of TGF-β in regulating LPC quiescence and activation. Spatial transcriptomics and single-cell sequencing revealed that LPCs receive multiple signals, particularly TGF-β, HGF, and EGF from surrounding hepatic stellate cells and macrophages in patients and zebrafish with MHN-induced ALF. Physiologically, TGF-β inhibits LPC proliferation by blocking the G1-S phase transition, an effect that was reversed by Smad7 overexpression in a murine injury model. Intriguingly, extensive LPC proliferation was observed in ALF patients despite strong TGF-β-p-SMAD signaling. Immunostaining further revealed concurrent activation of HGF/MET, EGF/EGFR, and downstream STAT3/ERK pathways in LPCs. In vitro, HGF or EGF overcame TGF-β-mediated growth arrest and promoted LPC proliferation. Beyond acting as a mitogen, HGF additionally induced hepatocyte gene programs (e.g., Hnf4a, Hnf1a) in LPCs. Strikingly, TGF-β signaling was required for HGF-dependent hepatocyte gene induction, indicating a dual role in restraining LPC proliferation and promoting functional maturation. These findings position TGF-β as a context-dependent determinant of LPC activation and lineage specification during ALF.

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