Deactivation of Hepatic Stellate Cells During Liver Fibrosis Resolution in Mice

Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York.
Gastroenterology (Impact Factor: 16.72). 06/2012; 143(4):1073-1083.e22. DOI: 10.1053/j.gastro.2012.06.036
Source: PubMed


Activated hepatic stellate cells (HSCs), the main fibrogenic cell type in the liver, undergo apoptosis after cessation of liver injury, which contributes to resolution of fibrosis. In this study, we investigated whether HSC deactivation constitutes an additional mechanism of liver fibrosis resolution.
HSC activation and deactivation were investigated by single-cell PCR and genetic tracking in transgenic mice that expressed a tamoxifen-inducible CreER under control of the endogenous vimentin promoter (Vimentin-CreER).
Single-cell quantitative polymerase chain reaction demonstrated activation of almost the entire HSC population in fibrotic livers, and a gradual decrease of HSC activation during fibrosis resolution, indicating deactivation of HSCs. Vimentin-CreER marked activated HSCs, demonstrated by a 6- to 16-fold induction of a membrane-bound green fluorescent protein (mGFP) Cre-reporter after injection of carbon tetrachloride, in liver and isolated HSCs, and a shift in localization of mGFP-marked HSCs from peri-sinusoidal to fibrotic septa. Tracking of mGFP-positive HSCs revealed the persistence of 40%-45% of mGFP expression in livers and isolated HSCs 30-45 days after carbon tetrachloride was no longer administered, despite normalization of fibrogenesis parameters; these findings confirm reversal of HSC activation. After fibrosis resolution, mGFP expression was observed again in desmin-positive peri-sinusoidal HSCs; no mGFP expression was detected in hepatocytes or cholangiocytes, excluding mesenchymal-epithelial transition. Notably, reverted HSCs remained in a primed state, with higher levels of responsiveness to fibrogenic stimuli.
In mice, reversal of HSC activation contributes to termination of fibrogenesis during fibrosis resolution, but results in higher responsiveness of reverted HSCs to recurring fibrogenic stimulation.

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    • "Moreover, probably around half of the myofibroblasts become inactivated and revert to a " quiescent-like " HSC phenotype, but these inactivated HSC remain " primed " , meaning that they can more easily be reactivated to become myofibroblasts upon fibrogenic stimuli [16] [17]. "

    Preview · Article · Jul 2015 · Journal of Hepatology
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    • "An increasingly comprehensive understanding of the molecular basis of hepatic fibrosis has emerged from studies, clarifying the regulation of hepatic stellate cell activation, and the immune and inflammatory responses in liver injury. Characterization of the reversion of activation in stellate cells during regression of fibrosis [29] [30], the control of stellate cell activation by epigenetic modulations that are transmissible from parent to offspring [31], and the roles of adipokines, hormones and cytokines in driving stellate cell responses [32] [33] are among the key findings that have begun to shed light on this fascinating cell type. At the same time, new insights have arisen about the impact of inflammatory cell subsets on fibrosis dynamics [34] [35] [36], and the importance of matrix cross-linking [37]. "

    Preview · Article · Dec 2014 · Journal of Hepatology
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    • "In the normal liver, hepatic stellate cells (HSCs) are myofibroblasts located in the space of Disse. Quiescent HSCs are primarily responsible for storing huge amounts of vitamin A in lipid droplets [4]-[6]. Activation of HSCs is the contributing cause of liver fibrogenesis and characterized by phenotypic transformation with diverse functional changes, including proliferation, contractility, cytokine secretion, chemotaxis, fibrogenesis, and matrix degradation [6]. "
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    ABSTRACT: Background Anti-inflammation via inhibition of NF-κB pathways in hepatic stellate cells (HSCs) is one therapeutic approach to hepatic fibrosis. Tanshinone IIA (C19H18O3, Tan IIA) is a lipophilic diterpene isolated from Salvia miltiorrhiza Bunge, with reported anti-inflammatory activity. We tested whether Tan IIA could inhibit HSC activation. Materials and Methods The cell line of rat hepatic stellate cells (HSC-T6) was stimulated with lipopolysaccharide (LPS) (100 ng/ml). Cytotoxicity was assessed by MTT assay. HSC-T6 cells were pretreated with Tan IIA (1, 3 and 10 µM), then induced by LPS (100 ng/ml). NF-κB activity was evaluated by the luciferase reporter gene assay. Western blotting analysis was performed to measure NF-κB-p65, and phosphorylations of MAPKs (ERK, JNK, p38). Cell chemotaxis was assessed by both wound-healing assay and trans-well invasion assay. Quantitative real-time PCR was used to detect gene expression in HSC-T6 cells. Results All concentrations of drugs showed no cytotoxicity against HSC-T6 cells. LPS stimulated NF-κB luciferase activities, nuclear translocation of NF-κB-p65, and phosphorylations of ERK, JNK and p38, all of which were suppressed by Tan IIA. In addition, Tan IIA significantly inhibited LPS-induced HSCs chemotaxis, in both wound-healing and trans-well invasion assays. Moreover, Tan IIA attenuated LPS-induced mRNA expressions of CCL2, CCL3, CCL5, IL-1β, TNF-α, IL-6, ICAM-1, iNOS, and α-SMA in HSC-T6 cells. Conclusion Our results demonstrated that Tan IIA decreased LPS-induced HSC activation.
    Full-text · Article · Jul 2014 · PLoS ONE
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