Enhanced Wnt Signalling in Hepatocytes is Associated with Schistosoma japonicum Infection and Contributes to Liver Fibrosis

Qi Wang,Shengjun Lu,Jiahui Lei,Yonglong Li,Xin Chou,Zhengming Fang,Fei Guan,Wenqi Liu

doi:10.1038/s41598-017-00377-4

Qi Wang, Shengjun Lu + Show 6 more

Open Access

https://doi.org/10.1038/s41598-017-00377-4

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Abstract

Liver fibrosis is the most serious pathology caused by Schistosoma japonicum infection, which arises when schistosome eggs are deposited in the liver. Eosinophils, macrophages and hepatic stellate cells (HSCs) have been identified as major cellular contributors to the development of granulomas and fibrosis, but little is known about the effects of hepatocytes on granuloma formation. Here, we found that the levels of Wnt signalling-related molecules, transforming growth factor β (TGF-β) and connective tissue growth factor (CTGF) in hepatocytes were markedly elevated after S. japonicum infection. Liver fibrosis was exacerbated when exogenous Wnt3a was introduced, but was alleviated when Wnt signalling was suppressed by DKK1, accompanied by the reduced expression of TGF-β and CTGF in hepatocytes. These results indicate that the hepatocytic expression of TGF-β and CTGF is mediated by Wnt signalling. Additionally, the hepatocytes isolated from infected mice promoted the activation of primary HSCs in vitro, however, this effect was not observed when hepatocytes from DKK1 treated S. japonicum-infected mice was employed in the co-culture system. Our findings identify a novel pro-fibrogenic role of hepatocytes in schistosomiasis-induced liver fibrosis that is dependent on Wnt signalling, which may serve as a potential target for ameliorating hepatic fibrosis caused by helminths.

Highlights

Frizzled[2] (Fz2)] were found to be upregulated in activated hepatic stellate cells compared with quiescent hepatic stellate cells[17]
These results suggest that both canonical and non-canonical Wnt signalling in hepatocytes was obviously induced after egg deposition, and this signalling was involved in the development of schistosomiasis
This study focused on exploring which signalling pathway(s) are critical to the activation of hepatic stellate cells (HSCs) and how they affect the development of liver fibrosis

Summary

Introduction

Frizzled[2] (Fz2)] were found to be upregulated in activated hepatic stellate cells compared with quiescent hepatic stellate cells[17]. As a major functional portion, liver parenchymal cells are inevitably involved in liver injury and fibrotic regeneration It is still unknown whether S. japonicum eggs affect the fate of hepatocytes, and the role of hepatocytes in liver fibrosis caused by S. japonicum infection remains to be determined. It has been reported that six Wnt proteins (Wnt[2], Wnt[4], Wnt5a, Wnt5b, Wnt9a and Wnt9b) and five Fz molecules (Fz2, Fz4, Fz6, Fz7 and Fz8) are expressed in hepatocytes isolated from normal liver tissue[20] This finding suggests that hepatocyte-derived Wnt molecules have the potential to activate Wnt signalling in hepatocytes or other resident liver cells. Our results reveal a previously unknown pro-fibrogenic function of hepatocytes in which Wnt signalling in hepatocytes appears to promote liver fibrogenesis resulting from S. japonicum infection by inducing the expression of TGF-β and CTGF

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