Our data provide evidence that MAIT cells in AILD patients have evolved towards an exhausted, profibrogenic phenotype and can contribute to the development of HSC-mediated liver fibrosis. These findings reveal a cellular and molecular pathway for fibrosis development in AILD that could be exploited for antifibrotic therapy. (Hepatology 2018;68:172-186).
Liver fibrosis and cirrhosis resulting from long-standing liver damage represents a major health care burden worldwide. To date, there is no anti-fibrogenic agent available, making liver transplantation the only curative treatment for decompensated cirrhotic liver disease. Liver fibrosis can result from different underlying chronic liver disease, such as chronic viral infection, excessive alcohol consumption, fatty liver disease or autoimmune liver diseases. It is becoming increasingly recognised that as a result from different pathogenic mechanisms liver fibrosis must be considered as many different diseases for which individual treatment strategies need to be developed. Moreover, the pathogenic changes of both liver architecture and vascularisation in cirrhotic livers, as well as the lack of "true-to-life" in vitro models have impeded the development of an effective anti-fibrogenic drug. Thus, in order to identify an efficient anti-fibrogenic compound, novel in-vitro models mimicking the interplay between pro-fibrogenic cell populations, immune cells and, importantly, the extracellular matrix need to be developed.
An altered liver microenvironment characterized by a dysregulated extracellular matrix (ECM) supports the development and progression of hepatocellular carcinoma (HCC). The development of experimental platforms able to reproduce these physio-pathological conditions is essential in order to identify and validate new therapeutic targets for HCC. The aim of this work was to validate a new in vitro model based on engineering three-dimensional (3D) healthy and cirrhotic human liver scaffolds with HCC cells recreating the micro-environmental features favoring HCC. Healthy and cirrhotic human livers ECM scaffolds were developed using a high shear stress oscillation-decellularization procedure. The scaffolds bio-physical/bio-chemical properties were analyzed by qualitative and quantitative approaches. Cirrhotic 3D scaffolds were characterized by biomechanical properties and microarchitecture typical of the native cirrhotic tissue. Proteomic analysis was employed on decellularized 3D scaffolds and showed specific enriched proteins in cirrhotic ECM in comparison to healthy ECM proteins. Cell repopulation of cirrhotic scaffolds highlighted a unique up-regulation in genes related to epithelial to mesenchymal transition (EMT) and TGFβ signaling. This was also supported by the presence and release of higher concentration of endogenous TGFβ1 in cirrhotic scaffolds in comparison to healthy scaffolds. Fibronectin secretion was significantly upregulated in cells grown in cirrhotic scaffolds in comparison to cells engrafted in healthy scaffolds. TGFβ1 induced the phosphorylation of canonical proteins Smad2/3, which was ECM scaffold-dependent. Important, TGFβ1-induced phosphorylation of Smad2/3 was significantly reduced and ECM scaffold-independent when pre/simultaneously treated with the TGFβ-R1 kinase inhibitor Galunisertib. In conclusion, the inherent features of cirrhotic human liver ECM micro-environment were dissected and characterized for the first time as key pro-carcinogenic components in HCC development.
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