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.

Evaluation of Gremlin-1 as a therapeutic target in metabolic dysfunction-associated steatohepatitis

“…However, the small subset of COL3A1+/THY1+ periportal fibroblasts unlikely represents the major fibrogenic cell subset in MASH. While periportal myofibroblasts play an important role in biliary fibrosis (28), in most chronic liver diseases such as MASH and alcohol-related liver disease, hepatic stellate cell (HSC)-derived myofibroblasts represent the predominant fibrogenic cell population (29). Moreover, hepatic Gremlin-1 expression is quite low when compared to organs such as the intestine or visceral adipose tissue (16).…”