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

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.