Review article: the signalling and functional role of the extracellular matrix in the development of liver fibrosis

Abstract

Summary Background Patients with liver fibrosis show a large heterogeneity, and for that reason effective treatments are still lacking. Emerging data suggest that there is more to fibrosis than previously understood. Opposed to earlier belief of being a passive scaffold for cells to reside in, the extracellular matrix (ECM) is now known to hold both signalling and functional properties important for the development of fibrosis. The interaction between the ECM and the collagen‐producing cells determines the course of the disease but is still poorly understood. Exploring the dynamics of this interplay will aid in the development of effective treatments. Aim To summarise and discuss the latest advances in the pathogenesis of liver fibrosis as well as key mediators of early disease progression. Methods Through literature search using databases including PubMed and Google Scholar, manuscripts published between 1961 and 2019 were included to assess both well‐established and recent theories of fibrosis development. Both pre‐clinical and clinical studies were included. Results Fibrosis alters the structure of the ECM releasing signalling fragments with the potential to escalate disease severity. In a diseased liver, hepatic stellate cells and other fibroblasts, together with hepatocytes and sinusoidal cells, produce an excessive amount of collagens. The cell‐to‐collagen interactions are unique in the different liver aetiologies, generating ECM profiles with considerable patient‐monitoring potential. Conclusions The local milieu in the injured area affects the course of fibrosis development in a site‐specific manner. Future research should focus on the dissimilarities in the ECM profile between different aetiologies of liver fibrosis.

Portal hypertension in cirrhosis: Pathophysiological mechanisms and therapy

“…The physical and chemical properties of the environment, in which HSCs are embedded, are also important for their activation (34), at least partly via Src and RhoA pathways (35). The majority of the fibrotic material is synthesized by HSC, and together with other cells they contribute to the perpetuated remodelling of the matrix, reviewed elsewhere (36,37). The stiffness of the matrix is provided, among other J o u r n a l P r e -p r o o f mechanisms, by the crosslinking of collagens, which leads to a less reversible fibrosis (38).…”

Evaluation of dithiothreitol-oxidizing capacity (DOC) as a serum biomarker for chronic hepatitis B in patients exhibiting normal alanine aminotransferase levels: a pilot study towards better monitoring of disease

“…[29À31] Moreover, the production of hydrogen peroxide by QSOX1 in the extracellular space may trigger inflammation [32]. With modulation of extracellular matrix being a hallmark of liver fibrosis and with hepatic stellate cells and portal fibroblasts being important sources of matrix proteins in hepatic fibrosis [33,34], it is possible that secreted QSOX1 is related to physiological responses to CLD. An important question is why the DOC assay shows better performance than the SOX assay, as both assays measure QSOX1-like activity.…”

Extracellular Matrix Remodeling in Chronic Liver Disease

“…Type VI collagen is a microfibrillar collagen found between the IM and the BM that can stimulate the proliferation of mesenchymal cells [ 66 , 67 ]. During liver fibrosis, it has been found that collagen VI is up to tenfold induced in liver fibrosis [ 68 ], and its signaling peptide endotrophin plays a crucial role in fibrosis.…”