Molecular interplays in hepatic stellate cells: apoptosis, senescence, and phenotype reversion as cellular connections that modulate liver fibrosis

Abstract

Liver fibrosis is a pathophysiological process correlated with intense repair and cicatrization mechanisms in injured liver, and over the past few years, the characterization of the fine-tuning of molecular interconnections that support the development of liver fibrosis has been investigated. In this cellular process, the hepatic stellate cells (HSCs) support the organ fibrogenesis. The HSCs are found in two distinct morpho-physiological states: quiescent and activated. In normal liver, most HSCs are found in quiescent state, presenting a considerable amount of lipid droplets in the cytoplasm, while in injured liver, the activated phenotype of HSCs is a myofibroblast, that secrete extracellular matrix elements and contribute to the establishment of the fibrotic process. Studies on the molecular mechanisms by which HSCs try to restore their quiescent state have been performed; however, no effective treatment to reverse fibrosis has been so far prescribed. Therefore, the elucidation of the cellular and molecular mechanisms of apoptosis, senescence, and the cell reversion phenotype process from activate to quiescent state will certainly contribute to the development of effective therapies to treat hepatic fibrosis. In this context, this review aimed to address central elements of apoptosis, senescence, and reversal of HSC phenotype in the control of hepatic fibrogenesis, as a guide to future development of therapeutic strategies.

Selonsertib Inhibits Liver Fibrosis via Downregulation of ASK1/ MAPK Pathway of Hepatic Stellate Cells

“…Since HSCs are the primary source of ECM that play a pivotal role in liver fibrogenesis, they attracted attention as critical target cells for antifibrotic therapy ( Higashi et al ., 2017 ). Decreasing the number of HSCs is considered as an essential strategy for clinical antifibrotic therapy, which can be achieved by inducing apoptosis of HSCs ( Elsharkawy et al ., 2005 ; Pellicoro et al ., 2014 ; de Oliveira da Silva et al ., 2017 ). Moreover, ASK1 is known to be associated with stress-induced apoptosis in inflammatory response ( Hatai et al ., 2000 ; Song et al ., 2013 ).…”

Role of Metabolism in Hepatic Stellate Cell Activation and Fibrogenesis

“…In this review, we provide a focused update on the impact of cellular metabolism on HSC activation and fibrogenesis. A detailed discussion on other signals and pathways is beyond the scope of this article and has been reviewed elsewhere ( Weiskirchen and Tacke, 2014 ; Lee et al, 2015 ; Wallace et al, 2015 ; Yang and Seki, 2015 ; El Taghdouini and van Grunsven, 2016 ; Hyun and Jung, 2016 ; Nwosu et al, 2016 ; Schumacher and Guo, 2016 ; de Oliveira da Silva et al, 2017 ; Higashi et al, 2017 ; Huang et al, 2017 ; Jiang et al, 2017 ; Kisseleva, 2017 ; Tsuchida and Friedman, 2017 ; Mortezaee, 2018 ; Ni et al, 2018 ; Wang J. N. et al, 2018 ).…”

Dynamic Changes in Function and Proteomic Composition of Extracellular Vesicles from Hepatic Stellate Cells during Cellular Activation

“…HSC undergo a phenotypic activation whereby they become contractile collagen-producing myofibroblasts that function either transiently in acute injury to produce a provisional matrix that supports hepatocyte repopulation or persistently in chronic injury to unrelentingly produce fibrotic material that causes scarring and exacerbates impaired liver function. These properties arise due to increased production and/or response by HSC of molecules involved in fibrogenesis, survival and inflammation [4]. The central role of HSC in fibrosis has spawned intense effort to target either key molecular mediators of fibrosis or the activated cells themselves (e.g., using cytotoxic agents) in a quest to develop new therapies for liver fibrosis [5,6].…”