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
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.
Available from: sciencedirect.com
- "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  , the control of stellate cell activation by epigenetic modulations that are transmissible from parent to offspring , and the roles of adipokines, hormones and cytokines in driving stellate cell responses   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   , and the importance of matrix cross-linking . "
Journal of Hepatology 12/2014; 61(6). DOI:10.1016/j.jhep.2014.08.039 · 11.34 Impact Factor
Available from: PubMed Central
- "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 -. 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 . "
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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.
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.
Our results demonstrated that Tan IIA decreased LPS-induced HSC activation.
PLoS ONE 07/2014; 9(7):e103229. DOI:10.1371/journal.pone.0103229 · 3.23 Impact Factor
Available from: Ping Wang
- "The previous concept was that the myofibroblasts undergo apoptosis on the basis of documented senescence during reversal of fibrosis. We (Kisseleva et al., 2012) and subsequently others (Troeger et al., 2012) have used genetic marking to demonstrate an alternative pathway in which myofibroblasts revert to a quiescent-like phenotype in CCl 4 -induced liver injury and experimental ALD. Genetic marking of myofibroblasts enabled the quantitative mapping of the fate of these cells in experimental models of fibrosis and its reversal. "
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ABSTRACT: Liver fibrosis results from dysregulation of normal wound healing, inflammation, activation of myofibroblasts, and deposition of extracellular matrix (ECM). Chronic liver injury causes death of hepatocytes and formation of apoptotic bodies, which in turn, release factors that recruit inflammatory cells (neutrophils, monocytes, macrophages, and lymphocytes) to the injured liver. Hepatic macrophages (Kupffer cells) produce TGFβ1 and other inflammatory cytokines that activate Collagen Type I producing myofibroblasts, which are not present in the normal liver. Secretion of TGFβ1 and activation of myofibroblasts play a critical role in the pathogenesis of liver fibrosis of different etiologies. Although the composition of fibrogenic myofibroblasts varies dependent on etiology of liver injury, liver resident hepatic stellate cells and portal fibroblasts are the major source of myofibroblasts in fibrotic liver in both experimental models of liver fibrosis and in patients with liver disease. Several studies have demonstrated that hepatic fibrosis can reverse upon cessation of liver injury. Regression of liver fibrosis is accompanied by the disappearance of fibrogenic myofibroblasts followed by resorption of the fibrous scar. Myofibroblasts either apoptose or inactivate into a quiescent-like state (e.g., stop collagen production and partially restore expression of lipogenic genes). Resolution of liver fibrosis is associated with recruitment of macrophages that secrete matrix-degrading enzymes (matrix metalloproteinase, collagenases) and are responsible for fibrosis resolution. However, prolonged/repeated liver injury may cause irreversible crosslinking of ECM and formation of uncleavable collagen fibers. Advanced fibrosis progresses to cirrhosis and hepatocellular carcinoma. The current review will summarize the role and contribution of different cell types to populations of fibrogenic myofibroblasts in fibrotic liver.
Frontiers in Pharmacology 07/2014; 5:167. DOI:10.3389/fphar.2014.00167 · 3.80 Impact Factor
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