The Role of Mesothelin in Activation of Portal Fibroblasts in Cholestatic Liver Injury

Abstract

Fibrosis is a common consequence of abnormal wound healing, which is characterized by infiltration of myofibroblasts and formation of fibrous scar. In liver fibrosis, activated Hepatic Stellate Cells (aHSCs) and activated Portal Fibroblasts (aPFs) are the major contributors to the origin of hepatic myofibroblasts. aPFs are significantly involved in the pathogenesis of cholestatic fibrosis, suggesting that aPFs may be a primary target for anti-fibrotic therapy in cholestatic injury. aPFs are distinguishable from aHSCs by specific markers including mesothelin (Msln), Mucin 16 (Muc16), and Thymus cell antigen 1 (Thy1, CD90) as well as fibulin 2, elastin, Gremlin 1, ecto-ATPase nucleoside triphosphate diphosphohydrolase 2. Msln plays a critical role in activation of PFs, via formation of Msln-Muc16-Thy1 complex that regulates TGFβ1/TGFβRI-mediated fibrogenic signaling. The opposing pro- and anti-fibrogenic effects of Msln and Thy1 are key components of the TGFβ1-induced activation pathway in aPFs. In addition, aPFs and activated lung and kidney fibroblasts share similarities across different organs with expression of common markers and activation cascade including Msln-Thy1 interaction. Here, we summarize the potential function of Msln in activation of PFs and development of cholestatic fibrosis, offering a novel perspective for anti-fibrotic therapy targeting Msln.

Keywords: activated Hepatic Stellate Cells; activated Portal Fibroblasts; cholestatic fibrosis.

Figure 1

Contribution of PFs and HSCs to hepatic myofibroblasts in response to liver injury. (a) PFs are located surrounding portal area, while HSCs are located in the space of Disse, which is a gap between sinusoidal endothelial cells and hepatocytes cluster. (b) PFs are primarily activated in response to cholestatic injury giving rise to Thy1⁺ aPFs/myofibroblasts which proliferate around portal area and form biliary fibrosis. HSCs are predominantly activated in response to hepatotoxic injury, and aHSCs infiltrate along the sinusoidal area and proliferate into parenchymal region forming a bridging fibrous scar.

Figure 2

Proposed model of Msln-Muc16-Thy1 interaction in (a) resting wild-type PFs, and TGFβ1-stimulated (b) wild-type, (c) Msln^−/−, and (d) Thy1^−/− aPFs. (a) Msln-Muc16 complex and Thy1-TGFβRI complex are formed in resting PFs. Binding of Thy1 to TGFβRI suppresses TGFβ1 signaling, while retaining Smad7 at the C-terminus of the TGFβRI. (b) In response to TGFβ1 signaling, Msln-Muc16 complex binds to Thy1, leading to dissociation of Thy1 from TGFβRI. TGFβ1 binding to TGFβRI and TGFβRII causes receptor crosslinking and binding of Smad2/3 to the receptors. Phosphorylated-Smad2/3 forms a complex with Smad4, and initiates transcription of target genes including Col1α1. (c) In Msln^−/− aPFs, increased affinity of Thy1 with TGFβRI hampers TGFβ1 binding to TGFβRI and TGFβRII, leading to attenuation of following phosphorylation of Smad2/3 and the downstream expression of Col1α1. (d) Thy1^−/− aPFs exhibit acceleration of Col1α1 synthesis in response to TGFβ1 stimulation due to the absence of Thy1 inhibition to TGFβRI, accompanied with increased phosphorylation of pSmad2/3 and reduced binding of Smad7 to TGFβRI.