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.

We investigated the role of mesothelin (Msln) and thymocyte differentiation antigen 1 (Thy1) in the activation of fibroblasts across multiple organs and demonstrated that Msln^-/- mice are protected from cholestatic fibrosis caused by Mdr2 (multidrug resistance gene 2) deficiency, bleomycin-induced lung fibrosis, and UUO (unilateral urinary obstruction)-induced kidney fibrosis. On the contrary, Thy1^-/- mice are more susceptible to fibrosis, suggesting that a Msln-Thy1 signaling complex is critical for tissue fibroblast activation. A similar mechanism was observed in human activated portal fibroblasts (aPFs). Targeting of human MSLN⁺ aPFs with two anti-MSLN immunotoxins killed fibroblasts engineered to express human mesothelin and reduced collagen deposition in livers of bile duct ligation (BDL)-injured mice. We provide evidence that antimesothelin-based therapy may be a strategy for treatment of parenchymal organ fibrosis.