Growth differentiation factor 11 attenuates liver fibrosis via expansion of liver progenitor cells

Abstract

ObjectiveLiver 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.DesignWe 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.ResultsWe 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.ConclusionCollectively, 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.

Liver progenitor cell-driven liver regeneration

“…41 ), are reported to regulate LPC activation. Growth factor signaling pathways, such as HGF/c-Met 42,43 , TGF-β 42,44,45 , FGF7 (ref. 46 ), and VEGF 47 signaling, are also involved in LPC activation and expansion ( Table 1).…”

Harnessing liver progenitors in the treatment of liver fibrosis: a step in the right direction?

“…The transforming growth factor beta (TGF-β) superfamily of proteins plays a critical role in the development and wound healing, and GDF11 is one such member. GDF11 has previously been reported to regulate progenitor cell growth in the developing retina, pancreas, and endothelium, and in this study by Dai et al , forced overexpression of GDF11 protected against liver fibrosis 7. However, members of the TGF-β family often exhibit apparent dichotomy in functionality.…”

“…In Gut , Dai and colleagues have extended our understanding of ‘progenitor-associated repair’ by elegantly showing that an (artificially induced) expanded liver progenitor cell population could ameliorate liver fibrosis in two murine models 7. Specifically, they showed that HSC-derived growth differentiation factor (GDF) 11 directly increased the number of leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5)+progenitors, which co-expressed other stem cell markers such as CD133 and Epcam, as well as the cholangiocyte marker Keratin19, and the hepatocyte marker hepatocyte nuclear factor (HNF) 4A, and thus resembled bi-potent liver progenitors recently described by others 4.…”

“…How could we reconcile these apparent differences in liver outcomes? One obvious explanation would be that the progenitor populations used in these studies are distinct from one another and Dai and colleagues had alluded to the possibility that ‘other facultative stem cells’ could be playing an antifibrotic role7 (figure 1).…”

Equal opportunity offer for all hepatocytes

“…5,17 Therefore, strategies enhancing expansion of these cells could overcome chronic liver injuries. 18 These studies provide solid evidence that hepatocytes located in various zones contribute equally to liver regeneration.…”