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.
journal_name
Gutjournal_title
Gutauthors
Dai Z,Song G,Balakrishnan A,Yang T,Yuan Q,Möbus S,Weiss AC,Bentler M,Zhu J,Jiang X,Shen X,Bantel H,Jaeckel E,Kispert A,Vogel A,Saborowski A,Büning H,Manns M,Cantz T,Ott M,Sharma ADdoi
10.1136/gutjnl-2019-318812subject
Has Abstractpub_date
2020-06-01 00:00:00pages
1104-1115issue
6eissn
0017-5749issn
1468-3288pii
gutjnl-2019-318812journal_volume
69pub_type
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