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

SIMPLE SUMMARY: Fibrosis is a common response to chronic tissue injury and plays a critical role in many diseases across medical subspecialties. To date, there are few therapies with limited effectiveness to treat fibrotic diseases. Expression of mesothelin was detected in activated Portal Fibroblasts, which are the major contributors to cholestatic liver fibrotic diseases such as primary and secondary biliary cholangitis and primary sclerosing cholangitis. This manuscript summarizes our most recent findings of the role of mesothelin in the pathogenesis of cholestatic fibrosis, and as a common mediator of tissue fibrosis. The function of mesothelin was linked to the activation of TGFβ1-mediated fibrogenic responses and FGF-induced proliferation of tissue fibroblasts. 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.