Molecular and cellular mechanisms of liver fibrosis and its regression
Tatiana Kisseleva & David Brenner
Nature Reviews Gastroenterology & Hepatology volume 18, pages151–166(2021)Cite this article
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Abstract
Chronic liver injury leads to liver inflammation and fibrosis, through which activated myofibroblasts in the liver secrete extracellular matrix proteins that generate the fibrous scar. The primary source of these myofibroblasts are the resident hepatic stellate cells. Clinical and experimental liver fibrosis regresses when the causative agent is removed, which is associated with the elimination of these activated myofibroblasts and resorption of the fibrous scar. Understanding the mechanisms of liver fibrosis regression could identify new therapeutic targets to treat liver fibrosis. This Review summarizes studies of the molecular mechanisms underlying the reversibility of liver fibrosis, including apoptosis and the inactivation of hepatic stellate cells, the crosstalk between the liver and the systems that orchestrate the recruitment of bone marrow-derived macrophages (and other inflammatory cells) driving fibrosis resolution, and the interactions between various cell types that lead to the intracellular signalling that induces fibrosis or its regression. We also discuss strategies to target hepatic myofibroblasts (for example, via apoptosis or inactivation) and the myeloid cells that degrade the matrix (for example, via their recruitment to fibrotic liver) to facilitate fibrosis resolution and liver regeneration.
Key points
Most chronic liver diseases, such as hepatitis C virus infection or non-alcoholic hepatic steatohepatitis, can progress to liver fibrosis with the formation of a fibrous scar.
Experimental and clinical liver fibrosis regresses with the removal of the aetiological agent or with new therapeutic interventions.
Chronic liver injury leads to activation of hepatic stellate cells, the major source of the fibrous scar in liver fibrosis.
Hepatic stellate cells have four known phenotypes — quiescent, activated, inactivated and senescent — each of which has a critical role in liver fibrosis and its regression.
During regression of liver fibrosis, activated hepatic stellate cells can undergo apoptosis or revert to an inactivated phenotype; the inactivated cells have a phenotype that is similar to but distinct from quiescent hepatic stellate cells.
Macrophages can promote fibrogenesis by the secretion of TGFβ and other agonists, but they also support the regression of fibrosis through the secretion of collagenases that resorb the fibrous scar.