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Original research
Growth differentiation factor 11 attenuates liver fibrosis via expansion of liver progenitor cells
  1. Zhen Dai1,2,
  2. Guangqi Song2,3,
  3. Asha Balakrishnan1,4,
  4. Taihua Yang1,2,
  5. Qinggong Yuan1,4,
  6. Selina Möbus1,2,
  7. Anna-Carina Weiss5,
  8. Martin Bentler6,
  9. Jimin Zhu3,
  10. Xuemei Jiang7,
  11. Xizhong Shen3,
  12. Heike Bantel1,
  13. Elmar Jaeckel1,
  14. Andreas Kispert5,
  15. Arndt Vogel1,
  16. Anna Saborowski1,
  17. Hildegard Büning6,
  18. Michael Manns1,
  19. Tobias Cantz1,8,
  20. Michael Ott1,4,
  21. Amar Deep Sharma1,2
  1. 1 Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
  2. 2 Research Group MicroRNA in Liver Regeneration, Cluster of Excellence REBIRTH, Hannover Medical School, Hannover, Germany
  3. 3 Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
  4. 4 Twincore Centre for Experimental and Clinical Infection Research, Hannover, Germany
  5. 5 Institute for Molecular Biology, Hannover Medical School, Hannover, Germany
  6. 6 Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany
  7. 7 Department of Gastroenterology, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, Haikou, China
  8. 8 Translational Hepatology and Stem Cell Biology, Cluster of Excellence REBIRTH, Hannover Medical School, Hannover, Germany
  1. Correspondence to Dr Amar Deep Sharma, Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; sharma.amar{at}mh-hannover.de; Professor Michael Ott; ott.michael{at}mh-hannover.de

Abstract

Objective 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.

  • fibrosis
  • myofibroblasts
  • chronic liver disease
  • stem cells
  • hepatic stellate cells
  • GDF11 and LGR5
http://creativecommons.org/licenses/by-nc/4.0/

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Footnotes

  • Contributors ADS conceived the idea, designed the study and provided the conceptual framework for the study. ZD, GS and QY performed all experiments and analysed the data. ADS wrote the manuscript with the help of ZD, MO, AB and AK. TY and SM helped with animal experiments and Western blot, respectively. A-CW and AK performed in situ hybridisation. GS, JZ, XJ and XS helped with collection and analysis of human fibrotic livers (China). HBantel and EJ provided human fibrotic liver samples (Germany). AS and AV generated human liver organoids. HBüning and MB cloned and provided AAV capsid variant for hepatic myofibroblasts. MM, TC and MO provided conceptual evaluation of the project. All authors commented on the manuscript and declared no conflicts of interest.

  • Funding The work was supported by the grants from Deutsche Forschungsgemeinschaft (DFG SH640/1-2, DFG EXC 62/2 and SFB-738) and Plus 3 Program of Boehringer Ingelheim. AB is supported from Deutsche Krebshilfe grant (111147). ZD and TY received stipends from China Scholarship Council.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval Allexperiments were performed according to the regulations of the Institutional Animal Care and Use Committee of the Hannover Medical School, Germany (Protocol number: TVA 17/2658) and Zhongshan Hospital of Fudan University, Shanghai, China.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

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