Molecular mechanism of hepatic stellate cell activation and antifibrotic therapeutic strategies

Abstract

Activation of hepatic stellate cells (HSCs) is the dominant event in liver fibrosis. The early events in the organization of HSC activation have been termed initiation. Initiation encompasses rapid changes in gene expression and phenotype that render the cells responsive to cytokines and other local stimuli. Cellular responses following initiation are termed perpetuation, which encompasses those cellular events that amplify the activated phenotype through enhanced growth factor expression and responsiveness. Multiple cells and cytokines play a part in the regulation of HSC activation. HSC activation consists of discrete phenotype responses, mainly proliferation, contractility, fibrogenesis, matrix degradation, chemotaxis and retinoid loss. Currently, antifibrotic therapeutic strategies include inhibition of HSC proliferation or stimulation of HSC apoptosis, downregulation of collagen production or promotion of its degradation, administration of cytokines, and infusion of mesenchymal stem cells. In this review, we summarize the latest advances in our understanding of the mechanisms of HSC activation and possible antifibrotic therapeutic strategies.

Retinol Binding Protein-Albumin Domain III Fusion Protein Deactivates Hepatic Stellate Cells

“…Upon liver injury, quiescent HSCs undergo phenotypic transition into myofibroblast-like cells, which is invariably associated with loss of cytoplasmic vitamin A-containing lipid droplets, positive staining for α-smooth muscle actin (α-SMA), and greatly increased synthesis of the ECM proteins (Friedman, 2008). Thus, HSCs are considered an attractive target for anti-fibrotic therapies (Bataller and Brenner, 2001;Li et al, 2008). Despite extensive investigations, there is, however, no effective therapy available at present for liver fibrosis and its end stage cirrhosis, except the removal of the causative agent and organ transplantation.…”

Anti-fibrotic effects of <i>Rhus javanica</i> Linn (Anacardiaceae) extract against Activated hepatic stellate cells via regulation of TGF-beta and smad signaling

“…Also, upregulation of collagen synthesis during activation is among the most striking molecular responses of HSCs to injury and is mediated by both transcriptional and post-transcriptional mechanisms. Transcriptional activation of type I collagen has been extensively characterized [14]. For that reason, HSCs plays a key role in hepatic fibrogenesis.…”

Treatment of the end Stage Liver Cirrhosis by Human Umbilical Cord Blood Stem Cells: Preliminary Results

“…Recent reports on pre-clinical and clinical studies suggested that LC could be reversible. HSCs activated upon liver injury are thought to be responsible for collagenogenesis and fibrosis in extracelluar matrix (124,125). Modulation of HSC activity (126.…”

“…Modulation of HSC activity (126. ), promotion of HSC apoptosis (127), blocking of matrix formation (128) or anti-proliferation measures on matrix fibrogenic and contractile response to HSC and degradation of established matrix (125,129) could be taken as potent strategies for reversal of LC. In addition to these strategies, stem cell therapy with multiple cytokine production and trans-differentiation potential would be a new option (130) for reversal of established LC.…”

“…So, the reduction of contractile response to HSC (141) would be a measure reducing critical complications induced by portal hypertension. Increasing the degradation of established matrix (125,142,142) would be an ideal strategy for reversal of LC.…”