The role of Mesothelin signaling in Portal Fibroblasts in the pathogenesis of cholestatic liver fibrosis.

Hiroaki Fuji,Rohit Loomba,Takahiro Nishio,Vivian Zhang,Yukinori Koyama,Kevin Lam,Grant Miller,David Brenner,Tatiana Kisseleva

doi:10.3389/fmolb.2021.790032

Hiroaki Fuji, Rohit Loomba + Show 7 more

Open Access

https://doi.org/10.3389/fmolb.2021.790032

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Abstract

Liver fibrosis develops in response to chronic toxic or cholestatic injury, and is characterized by apoptosis of damaged hepatocytes, development of inflammatory responses, and activation of Collagen Type I producing myofibroblasts that make liver fibrotic. Two major cell types, Hepatic Stellate Cells (HSCs) and Portal Fibroblasts (PFs) are the major source of hepatic myofibroblasts. Hepatotoxic liver injury activates Hepatic Stellate Cells (aHSCs) to become myofibroblasts, while cholestatic liver injury activates both aHSCs and Portal Fibroblasts (aPFs). aPFs comprise the major population of myofibroblasts at the onset of cholestatic injury, while aHSCs are increasingly activated with fibrosis progression. Here we summarize our current understanding of the role of aPFs in the pathogenesis of cholestatic fibrosis, their unique features, and outline the potential mechanism of targeting aPFs in fibrotic liver.

Highlights

Hepatic fibrosis is the outcome of chronic liver diseases, including cholestatic liver disease (primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), and secondary biliary cirrhosis (SBC)) (Lazaridis and LaRusso, 2016) and toxic liver injury (hepatitis B virus (HBV), hepatitis C virus (HCV), alcoholic liver disease and non-alcoholic steatohepatitis (NASH)) (Friedman, 2008; Dranoff and Wells, 2010)
We have recently demonstrated that Msln, mouse mucin 16 (Muc16) (Koyama et al, 2017), and Thy-1 (Katsumata et al, 2017) play a critical role in regulation of activated PFs (aPFs) biology
Hepatotoxic liver injury activates Hepatic stellate cells (HSCs) to become myofibroblasts, while cholestatic liver injury activates both HSCs and aPFs (Dranoff et al, 2002; Kruglov et al, 2002; Wen et al, 2012). aPFs comprise 70% of myofibroblasts at the onset of bile duct ligation (BDL)-induced injury, while activated HSCs (aHSCs) are increasingly activated with fibrosis progression (Iwaisako et al, 2014; Karin et al, 2016) (Figures 1A,B)

Summary

Introduction

Hepatic fibrosis is the outcome of chronic liver diseases, including cholestatic liver disease (primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), and secondary biliary cirrhosis (SBC)) (Lazaridis and LaRusso, 2016) and toxic liver injury (hepatitis B virus (HBV), hepatitis C virus (HCV), alcoholic liver disease and non-alcoholic steatohepatitis (NASH)) (Friedman, 2008; Dranoff and Wells, 2010). Cholestatic (but not toxic) injury (Desmoulière et al, 1997) causes their proliferation and differentiation into Collagen Type I-producing myofibroblasts( (Dranoff and Wells, 2010), (Desmoulière et al, 1997), (Yata et al, 2003)), suggesting that aPFs are the “first responders” to the cholestasis-induced fibrogenic liver injury.

Results

Conclusion