Growth differentiation factor 11 attenuates liver fibrosis via expansion of liver progenitor cells
- Zhen Dai1,2,
- Guangqi Song2,3,
- Asha Balakrishnan1,4,
- Taihua Yang1,2,
- Qinggong Yuan1,4,
- Selina Möbus1,2,
- Anna-Carina Weiss5,
- Martin Bentler6,
- http://orcid.org/0000-0002-2150-473XJimin Zhu3,
- Xuemei Jiang7,
- Xizhong Shen3,
- Heike Bantel1,
- Elmar Jaeckel1,
- Andreas Kispert5,
- Arndt Vogel1,
- Anna Saborowski1,
- Hildegard Büning6,
- Michael Manns1,
- Tobias Cantz1,8,
- Michael Ott1,4,
- http://orcid.org/0000-0003-3599-2372Amar Deep Sharma1,2
Author affiliations- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- Research Group MicroRNA in Liver Regeneration, Cluster of Excellence REBIRTH, Hannover Medical School, Hannover, Germany
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
- Twincore Centre for Experimental and Clinical Infection Research, Hannover, Germany
- Institute for Molecular Biology, Hannover Medical School, Hannover, Germany
- Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany
- Department of Gastroenterology, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, Haikou, China
- Translational Hepatology and Stem Cell Biology, Cluster of Excellence REBIRTH, Hannover Medical School, Hannover, Germany
AbstractObjective Liver fibrosis and cirrhosis resulting from chronic liver injury represent a major healthcare burden worldwide. Growth differentiation factor (GDF) 11 has been recently investigated for its role in rejuvenation of ageing organs, but its role in chronic liver diseases has remained unknown. Here, we investigated the expression and function of GDF11 in liver fibrosis, a common feature of most chronic liver diseases.
Design We analysed the expression of GDF11 in patients with liver fibrosis, in a mouse model of liver fibrosis and in hepatic stellate cells (HSCs) as well as in other liver cell types. The functional relevance of GDF11 in toxin-induced and cholestasis-induced mouse models of liver fibrosis was examined by in vivo modulation of Gdf11 expression using adeno-associated virus (AAV) vectors. The effect of GDF11 on leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5)+ liver progenitor cells was studied in mouse and human liver organoid culture. Furthermore, in vivo depletion of LGR5+ cells was induced by injecting AAV vectors expressing diptheria toxin A under the transcriptional control of Lgr5 promoter.
Results We showed that the expression of GDF11 is upregulated in patients with liver fibrosis and in experimentally induced murine liver fibrosis models. Furthermore, we found that therapeutic application of GDF11 mounts a protective response against fibrosis by increasing the number of LGR5+ progenitor cells in the liver.
Conclusion Collectively, our findings uncover a protective role of GDF11 during liver fibrosis and suggest a potential application of GDF11 for the treatment of chronic liver disease.
http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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http://dx.doi.org/10.1136/gutjnl-2019-318812
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Significance of this studyWhat is already known on this subject?Liver fibrosis and cirrhosis are common features of most chronic liver diseases and cause millions of deaths worldwide. Transforming growth factor β family members have been shown to play pivotal roles in fibrogenesis of the liver as well as in other organs. Till date, the function of growth differentiation factor (GDF) 11, a member of the transforming growth factor β family, during liver fibrosis has not been elucidated.
What are the new findings?The level of GDF11 is elevated in patients with liver fibrosis. Identification of activated hepatic stellate cells as the main source of hepatic GDF11 in vivo. The overexpression of GDF11 by adeno-associated virus vectors attenuates toxin-induced and cholestasis-induced liver fibrosis models, two independent modes of chronic liver injury. GDF11 attenuates liver fibrosis via augmenting expansion of liver progenitor cells in fibrotic mice.
How might it impact on clinical practice in the foreseeable future?
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发表于 2020-5-8 15:17
