Bone marrow-derived fibrocytes contribute to liver fibrosis

Chronic liver injury often leads to hepatic fibrosis, a condition associated with increased levels of circulating TGF-β1 and lipopolysaccharide, activation of myofibroblasts, and extensive deposition of extracellular matrix, mostly collagen Type I. Hepatic stellate cells are considered to be the major¹ but not the only source of myofibroblasts in the injured liver.² Hepatic myofibroblasts may also originate from portal fibroblasts, mesenchymal cells, and fibrocytes.³ Since the discovery of fibrocytes in 1994 by Dr. Bucala and colleagues, this bone marrow (BM)-derived collagen Type I-producing CD45⁺ cells remain the most fascinating cells of the hematopoietic system. Due to the ability to differentiate into collagen Type I producing cells/myofibroblasts, fibrocytes were implicated in the pathogenesis of liver, skin, lung, and kidney fibrosis. However, studies of different organs often contain controversial results on the number of fibrocytes recruited to the site of injury and their biological function. Furthermore, fibrocytes were implicated in the pathogenesis of sepsis and were shown to possess antimicrobial activity. Finally, in response to specific stimuli, fibrocytes can give rise to fully differentiated macrophages, suggesting that in concurrence with the high plasticity of hematopoietic cells, fibrocytes exhibit progenitor properties. Here, we summarize our current understanding of the role of CD45⁺Collagen Type I⁺ BM-derived cells in response to fibrogenic liver injury and septicemia and discuss the most recent evidence supporting the critical role of fibrocytes in the mediation of pro-fibrogenic and/or pro-inflammatory responses.     

Effect of human amniotic epithelial cells on pro‐fibrogenic resident hepatic cells in a rat model of liver fibrosis

Myofibroblasts are key fibrogenic cells responsible for excessive extracellular matrix synthesis characterizing the fibrotic lesion. In liver fibrosis, myofibroblasts derive either from activation of hepatic stellate cells (HSC) and portal fibroblasts (PF), or from the activation of fibroblasts that originate from ductular epithelial cells undergoing epithelial–mesenchymal transition. Ductular cells can also indirectly promote myofibroblast generation by activating TGF‐β, the main fibrogenic growth factor, through αvβ6 integrin. In addition, after liver injury, liver sinusoidal cells can lose their ability to maintain HSC quiescence, thus favouring HSC differentiation towards myofibroblasts. The amniotic membrane and epithelial cells (hAEC) derived thereof have been shown to decrease hepatic myofibroblast levels in rodents with liver fibrosis. In this study, in a rat model of liver fibrosis, we investigated the effects of hAEC on resident hepatic cells contributing to myofibroblast generation. Our data show that hAEC reduce myofibroblast numbers with a consequent reduction in fibronectin and collagen deposition. Interestingly, we show that hAEC strongly act on specific myofibroblast precursors. Specifically, hAEC reduce the activation of PF rather than HSC. In addition, hAEC target reactive ductular cells by inhibiting their proliferation and αvβ6 integrin expression, with a consequent decrease in TGF‐β activation. Moreover, hAEC counteract the transition of ductular cells towards fibroblasts, while it does not affect injury‐induced and fibrosis‐promoting sinusoidal alterations. In conclusion, among the emerging therapeutic applications of hAEC in liver diseases, their specific action on PF and ductular cells strongly suggests their application in liver injuries involving the expansion and activation of the portal compartment.     

Autocrine release of TGF-beta by portal fibroblasts regulates cell growth

Portal fibroblasts (PF) are a newly isolated population of fibrogenic cells in the liver postulated to play a significant role in early biliary fibrosis. Because transforming growth factor-beta (TGF)-beta is a key growth factor in fibrosis, we characterized the response of PF to TGF-beta. We demonstrate that PF produce significant amounts of TGF-beta2 and, unlike activated hepatic stellate cells (HSC), express all three TGF-beta receptors and are growth inhibited by TGF-beta1 and TGF-beta2. Fibroblast growth factor (FGF)-2, but not platelet derived growth factor (PDGF), causes PF proliferation. These data suggest a mechanism whereby HSC eclipse PF as the dominant myofibroblast population in biliary fibrosis.     

Origins and functions of liver myofibroblasts

Myofibroblasts combine the matrix-producing functions of fibroblasts and the contractile properties of smooth muscle cells. They are the main effectors of fibrosis in all tissues and make a major contribution to other aspects of the wound healing response, including regeneration and angiogenesis. They display the de novo expression of α-smooth muscle actin. Myofibroblasts, which are absent from the normal liver, are derived from two major sources: hepatic stellate cells (HSCs) and portal mesenchymal cells in the injured liver. Reliable markers for distinguishing between the two subpopulations at the myofibroblast stage are currently lacking, but there is evidence to suggest that both myofibroblast cell types, each exposed to a particular microenvironment (e.g. hypoxia for HSC-MFs, ductular reaction for portal mesenchymal cell-derived myofibroblasts (PMFs)), expand and exert specialist functions, in scarring and inflammation for PMFs, and in vasoregulation and hepatocellular healing for HSC-MFs. Angiogenesis is a major mechanism by which myofibroblasts contribute to the progression of fibrosis in liver disease. It has been clearly demonstrated that liver fibrosis can regress, and this process involves a deactivation of myofibroblasts, although probably not to a fully quiescent phenotype. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.     

Cells with morphological and immunohistochemical features of hepatic stellate cells (Ito cells) form an extralittoral (extrasinusoidal) compartment in the cirrhotic rat liver.

Systematic studies on hepatic stellate cells and myofibroblasts have so far mainly focused on cells located in the perisinusoidal space of Disse, the so-called littoral compartment. Here, these cells play a key role for intralobular fibrogenesis and sinusoidal capillarization. However, advanced hepatic fibrosis and cirrhosis are characterized by portal tract fibrosis and septal fibrosis, thus involving cells outside the perisinusoidal space. To study the question as to whether hepatic stellate cells occur and are expanded in an extralittoral (extrasinusoidal) compartment in cirrhogenesis, we systematically analyzed the distribution and density of desminreactive stellate cells in a rat model of hepatic fibrosis. Fibrosis and remodeling of the liver were induced by bile duct ligation, and stellate cells were identified by single and double immunohistochemistry. We can show that desmin-reactive cells are reproducibly detectable in extralittoral compartments of the normal and fibrotic rat liver. Periductular extralittoral stellate cells are significantly more frequent in cirrhosis, indicating that extralittoral stellate cells expand in concert with proliferating ductules. The findings suggest that ductular proliferation thought to represent a pacemaker of hepatic remodeling is accompanied by a population of cells exhibiting the same phenotype as perisinusoidal stellate cells.     

肝纤维化发病机制中细胞和分子机制的研究进展

关于肝纤维化形成的复杂的细胞和分子联系已经有了相当多的研究进展。最近的数据表明,纤维化进程的终止和纤维分解途径的恢复可以逆转晚期肝纤维化甚至肝硬化。因此,需要更好地阐明参与肝纤维化的细胞和分子机制。HSC(肝星状细胞)的激活是肝纤维化发生的中心事件,此外还有产生基质的其他细胞来源,包括肝门区的成纤维细胞,纤维细胞和骨髓来源的肌纤维母细胞。这些细胞与其邻近细胞通过多种联系聚集产生纤维疤痕并造成持续性损伤。阐明不同类型的细胞的相互作用,揭示细胞因子对这些细胞的影响,理清活化HSC基因表达的调控,将有助于我们探索新的肝纤维化治疗靶点。此外,不同的病因有不同的致病途径,弄清这一点有助于针对特异性疾病治疗方法的发现。本文概述了肝纤维化的细胞和分子机制的最新研究进展,可能为未来治疗方法带来新的突破。     

Seven Steps to Stellate Cells

Hepatic stellate cells are liver-resident cells of star-like morphology and are located in the space of Disse between liver sinusoidal endothelial cells and hepatocytes^1,2. Stellate cells are derived from bone marrow precursors and store up to 80% of the total body vitamin A^{1, 2}. Upon activation, stellate cells differentiate into myofibroblasts to produce extracellular matrix, thus contributing to liver fibrosis³. Based on their ability to contract, myofibroblastic stellate cells can regulate the vascular tone associated with portal hypertension⁴. Recently, we demonstrated that hepatic stellate cells are potent antigen presenting cells and can activate NKT cells as well as conventional T lymphocytes⁵. Here we present a method for the efficient preparation of hepatic stellate cells from mouse liver. Due to their perisinusoidal localization, the isolation of hepatic stellate cells is a multi-step process. In order to render stellate cells accessible to isolation from the space of Disse, mouse livers are perfused in situ with the digestive enzymes Pronase E and Collagenase P. Following perfusion, the liver tissue is subjected to additional enzymatic treatment with Pronase E and Collagenase P in vitro. Subsequently, the method takes advantage of the massive amount of vitamin A-storing lipid droplets in hepatic stellate cells. This feature allows the separation of stellate cells from other hepatic cell types by centrifugation on an 8% Nycodenz gradient. The protocol described here yields a highly pure and homogenous population of stellate cells. Purity of preparations can be assessed by staining for the marker molecule glial fibrillary acidic protein (GFAP), prior to analysis by fluorescence microscopy or flow cytometry. Further, light microscopy reveals the unique appearance of star-shaped hepatic stellate cells that harbor high amounts of lipid droplets. Taken together, we present a detailed protocol for the efficient isolation of hepatic stellate cells, including representative images of their morphological appearance and GFAP expression that help to define the stellate cell entity.Download video file.^{(41M, mov)}     

Silencing p53 inhibits interleukin 10-induced activated hepatic stellate cell senescence and fibrotic degradation in vivo

Activated hepatic stellate cells are reported to play a significant role in liver fibrogenesis. Beside the phenotype reversion and apoptosis of activated hepatic stellate cells, the senescence of activated hepatic stellate cells limits liver fibrosis. Our previous researches have demonstrated that interleukin-10 could promote hepatic stellate cells senescence via p53 signaling pathway in vitro. However, the relationship between expression of p53 and senescence of activated hepatic stellate cells induced by interleukin-10 in fibrotic liver is unclear. The purpose of present study was to explore whether p53 plays a crucial role in the senescence of activated hepatic stellate cells and degradation of collagen mediated by interleukin-10. Hepatic fibrosis animal model was induced by carbon tetrachloride through intraperitoneal injection and transfection of interleukin-10 gene to liver was performed by hydrodynamic-based transfer system. Depletions of p53 in vivo and in vitro were carried out by adenovirus-based short hairpin RNA against p53. Regression of fibrosis was assessed by liver biopsy and collagen staining. Cellular senescence in the liver was observed by senescence-associated beta-galactosidase (SA-β-Gal) staining. Immunohistochemistry, immunofluorescence double staining, and Western blot analysis were used to evaluate the senescent cell and senescence-related protein expression. Our data showed that interleukin-10 gene treatment could lighten hepatic fibrosis induced by carbon tetrachloride and induce the aging of activated hepatic stellate cells accompanied by up-regulating the expression of aging-related proteins. We further demonstrated that depletion of p53 could abrogate up-regulation of interleukin-10 on the expression of senescence-related protein in vivo and vitro. Moreover, p53 knockout in fibrotic mice could block not only the senescence of activated hepatic stellate cells, but also the degradation of fibrosis induced by interleukin-10 gene intervention. Taken together, our results suggested that interleukin-10 gene treatment could attenuate carbon tetrachloride-induced hepatic fibrosis by inducing senescence of activated hepatic stellate cells in vivo, and this induction was closely related to p53 signaling pathway.     

The anti-fibrotic effects of CCN1/CYR61 in primary portal myofibroblasts are mediated through induction of reactive oxygen species resulting in cellular senescence,apoptosis and attenuated TGF-β signaling

Cysteine-rich protein 61 (CCN1/CYR61) is a CCN (CYR61, CTGF (connective tissue growth factor), and NOV (Nephroblastoma overexpressed gene)) family matricellular protein comprising six secreted CCN proteins in mammals. CCN1/CYR61 expression is associated with inflammation and injury repair. Recent studies show that CCN1/CYR61 limits fibrosis in models of cutaneous wound healing by inducing cellular senescence in myofibroblasts of the granulation tissue which thereby transforms into an extracellular matrix-degrading phenotype. We here investigate CCN1/CYR61 expression in primary profibrogenic liver cells (i.e., hepatic stellate cells and periportal myofibroblasts) and found an increase of CCN1/CYR61 expression during early activation of hepatic stellate cells that declines in fully transdifferentiated myofibroblasts. By contrast, CCN1/CYR61 levels found in primary parenchymal liver cells (i.e., hepatocytes) were relatively low compared to the levels exhibited in hepatic stellate cells and portal myofibroblasts. In models of ongoing liver fibrogenesis, elevated levels of CCN1/CYR61 were particularly noticed during early periods of insult, while expression declined during prolonged phases of fibrogenesis. We generated an adenovirus type 5 encoding CCN1/CYR61 (i.e., Ad5-CMV-CCN1/CYR61) and overexpressed CCN1/CYR61 in primary portal myofibroblasts. Interestingly, overexpressed CCN1/CYR61 significantly inhibited production of collagen type I at both mRNA and protein levels as evidenced by quantitative real-time polymerase chain reaction, Western blot and immunocytochemistry. CCN1/CYR61 further induces production of reactive oxygen species (ROS) leading to dose-dependent cellular senescence and apoptosis. Additionally, we demonstrate that CCN1/CYR61 attenuates TGF-β signaling by scavenging TGF-β thereby mitigating in vivo liver fibrogenesis in a bile duct ligation model. Conclusion: In line with dermal fibrosis and scar formation, CCN1/CYR61 is involved in liver injury repair and tissue remodeling. CCN1/CYR61 gene transfer into extracellular matrix-producing liver cells is therefore potentially beneficial in liver fibrotic therapy.     

Hepatic fibrosis and cirrhosis: the (myo)fibroblastic cell subpopulations involved

Fibrosis, defined as the excessive deposition of extracellular matrix in an organ, is the main complication of chronic liver damage. Its endpoint is cirrhosis, which is responsible for significant morbidity and mortality. The accumulation of extracellular matrix observed in fibrosis and cirrhosis is due to the activation of fibroblasts, which acquire a myofibroblastic phenotype. Myofibroblasts are absent from normal liver. They are produced by the activation of precursor cells, such as hepatic stellate cells and portal fibroblasts. These fibrogenic cells are distributed differently in the hepatic lobule: the hepatic stellate cells resemble pericytes and are located along the sinusoids, in the Disse space between the endothelium and the hepatocytes, whereas the portal fibroblasts are embedded in the portal tract connective tissue around portal structures (vessels and biliary structures). Differences have been reported between these two fibrogenic cell populations, in the mechanisms leading to myofibroblastic differentiation, activation and "deactivation", but confirmation is required. Second-layer cells surrounding centrolobular veins, fibroblasts present in the Glisson capsule surrounding the liver, and vascular smooth muscle cells may also express a myofibroblastic phenotype and may be involved in fibrogenesis. It is now widely accepted that the various types of lesion (e.g., lesions caused by alcohol abuse and viral hepatitis) leading to liver fibrosis involve specific fibrogenic cell subpopulations. The biological and biochemical characterisation of these cells is thus essential if we are to understand the mechanisms underlying the progressive development of excessive scarring in the liver. These cells also differ in proliferative and apoptotic capacity, at least in vitro. All this information is required for the development of treatments specifically and efficiently targeting the cells responsible for the development of fibrosis/cirrhosis.     

Thy-1 is expressed in myofibroblasts but not found in hepatic stellate cells following liver injury

Thy-1 (CD90) is an adhesion molecule induced in fibroblast populations associated with wound healing and fibrosis. In this study the question whether Thy-1-gene-expression can be induced in hepatic stellate cells (HSC) in vivo, under conditions of liver injury or liver regeneration was addressed. Acute and chronic rat liver injury was induced by the administration of CCl₄. For comparison, cirrhotic human liver, and rat 67% partial hepatectomy (PH) was studied as well. Thy-1-gene-expression was examined also in isolated human liver myofibroblasts. Thy-1-mRNA expression was significantly upregulated in chronic liver injury. Thy-1⁺ cells were detected in the periportal area of rat liver specimens in normal-, injured- and regenerative-conditions. In chronic human and rat liver injury, Thy-1⁺ cells were located predominantly in scar tissue. In the pericentral necrotic zone after CCl₄-treatment, no induction of Thy-1 was found. Gremlin and Thy-1 showed comparable localization in the periportal areas. Thy-1 was not detected in either normal or capillarized sinusoids, in isolated rat HSC, and was neither inducible by inflammatory cytokines in isolated HSC, nor upregulated in treated myofibroblasts. Based upon these data Thy-1 is not a marker of “activated” sinusoidal HSC, but it is a marker of “activated” (myo)fibroblasts found in portal areas and in scar tissue. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Fasting reduces liver fibrosis in a mouse model for chronic cholangiopathies

Chronic cholangiopathies often lead to fibrosis, as a result of a perpetuated wound healing response, characterized by increased inflammation and excessive deposition of proteins of the extracellular matrix. Our previous studies have shown that food deprivation suppresses the immune response, which led us to postulate its beneficial effects on pathology in liver fibrosis driven by portal inflammation. We investigated the consequences of fasting on liver fibrosis in Abcb4^?/? mice that spontaneously develop it due to a lack of phospholipids in bile. The effect of up to 48 h of food deprivation was studied by gene expression profiling, (immuno)histochemistry, and biochemical assessments of biliary output, and hepatic and plasma lipid composition. In contrast to increased biliary output in the wild type counterparts, bile composition in Abcb4^?/? mice remained unchanged with fasting and did not influence the attenuation of fibrosis. Markers of inflammation, however, dramatically decreased in livers of Abcb4^?/? mice already after 12 h of fasting. Reduced presence of activated hepatic stellate cells and actively increased tissue remodeling further propelled a decrease in parenchymal fibrosis in fasting. This study is the first to show that food deprivation positively influences liver pathology in a fibrotic mouse model for chronic cholangiopathies, opening a door for new strategies to improve liver regeneration in chronic disease.     

Secretion of MCP-1/CCL2 by bile duct epithelia induces myofibroblastic transdifferentiation of portal fibroblasts

Portal fibroblasts (PF) are fibrogenic liver cells distinct from hepatic stellate cells (HSC). Recent evidence suggests that PF may be important mediators of biliary fibrosis and cirrhosis. The cytokine monocyte chemoattractant protein-1 (MCP-1)/CCL2 is upregulated in biliary fibrosis by bile duct epithelia (BDE) and induces functional responses in HSC. Thus we hypothesized that release of MCP-1 may mediate biliary fibrosis. We report that PF express functional receptors for MCP-1 that are distinct from the receptor CCR2. MCP-1 induces proliferation, increase and redistribution of alpha-smooth muscle (alpha-SMA) expression, loss of the ectonucleotidase NTPDase2, and upregulation of alpha(1)-procollagen production in PF. BDE secretions induce alpha-SMA levels in PF, and this is inhibited by MCP-1 blocking antibody. Together, these data suggest that BDE regulate PF proliferation and myofibroblastic transdifferentiation in a paracrine fashion via release of MCP-1.     

Hepatitis C virus RNA replication in human stellate cells regulates gene expression of extracellular matrix-related molecules

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, including chronic hepatitis, fibrosis, and cirrhosis. Fibrosis often develops in HCV-infected livers and ultimately leads to cirrhosis and carcinoma. During fibrosis, hepatic stellate cells (HSC) play important roles in the control of extracellular matrix synthesis and degradation in fibrotic livers. In this study, we established a subgenomic replicon (SGR) cell line with human hepatic stellate cells to investigate the effect of HCV RNA replication on HSC. Isolated SGR clones contained HCV RNA copy numbers ranging from 10⁴ to 10⁷ per μg total RNA, and long-term culture of low-copy number SGR clones resulted in markedly increased HCV RNA copy numbers. Furthermore, HCV RNA replication affected gene expression of extracellular matrix-related molecules in both hepatic stellate cells and hepatic cells, suggesting that HCV RNA replication and/or HCV proteins directly contribute to liver fibrosis. The HCV RNA-replicating hepatic stellate cell line isolated in this study will be useful for investigating hepatic stellate cell functions and HCV replication machinery.     

Induction of cell death in activated hepatic stellate cells by targeted gene expression of the thymidine kinase/ganciclovir system

Liver fibrosis is the result from a relative imbalance between synthesis and degradation of matrix proteins. Following liver injury of any etiology, hepatic stellate cells undergo a response known as activation, which is the transition of quiescent cells into proliferative, fibrogenic, and contractile myofibroblasts. Upon this cellular transdifferentiation the effector cell becomes the major source of fibrillar and non-fibrillar matrix proteins resulting in excessive scar formation and cirrhosis, the end stage of fibrosis. Concomitant with progressive liver fibrosis, the tissue inhibitor of metalloproteinases-1 (TIMP-1) is strongly activated in hepatic stellate cells. We have developed a recombinant replication-defective adenovirus in which the TIMP-1 promoter is coupled to the herpes simplex virus thymidine kinase gene rendering activated hepatic stellate cells susceptible to ganciclovir. This novel targeted suicide gene approach was validated in a culture model considered to reflect an accelerated time course of the cellular and molecular events that occur during liver fibrosis. We demonstrate that transfer of the suicide gene to culture-activated hepatic stellate cells results in a strong expression of the respective transgene as assessed by Northern blot and Western blot analyses. The enzyme catalyzed the proper conversion of its prodrug subsequently initiating programmed cell death as estimated by caspase-3 assay and Annexin V-Fluos staining. Altogether, these results indicate that induction of programmed cell death is a promising approach to eliminate fibrogenic HSC.     

Schistosoma japonicum soluble egg antigens induce apoptosis and inhibit activation of hepatic stellate cells: a possible molecular mechanism

Hepatic stellate cells play a key role in the development of hepatic fibrosis. Activated hepatic stellate cells can be reversed to a quiescent-like state or apoptosis can be induced to reverse fibrosis. Some studies have recently shown that Schistosoma mansoni eggs could suppress the activation of hepatic stellate cells and that soluble egg antigens from schistosome eggs could promote immunocyte apoptosis. Hence, in this study, we attempt to assess the direct effects of Schistosoma japonicum soluble egg antigens on hepatic stellate cell apoptosis, and to explore the mechanism by which the apoptosis of activated hepatic stellate cells can be induced by soluble egg antigens, as well as the mechanism by which hepatic stellate cell activation is inhibited by soluble egg antigens. Here, it was shown that S. japonicum-infected mouse livers had increased apoptosis phenomena and a variability of peroxisome proliferator-activated receptor γ expression. Soluble egg antigens induce morphological changes in the hepatic stellate cell LX-2 cell line, inhibit cell proliferation and induce cell-cycle arrest at the G₁ phase. Soluble egg antigens also induce apoptosis in hepatic stellate cells through the TNF-related apoptosis-inducing ligand/death receptor 5 and caspase-dependent pathways. Additionally, soluble egg antigens could inhibit the activation of hepatic stellate cells through peroxisome proliferator-activated receptor γ and the transforming growth factor β signalling pathways. Therefore, our study provides new insights into the anti-fibrotic effects of S. japonicum soluble egg antigens on hepatic stellate cell apoptosis and the underlying mechanism by which the liver fibrosis could be attenuated by soluble egg antigens.     

Overexpression of c-myc in hepatocytes promotes activation of hepatic stellate cells and facilitates the onset of liver fibrosis

BackgroundLiver fibrosis is a consequence of chronic liver injury and can further progress to hepatocellular carcinoma (HCC). Fibrogenesis involves activation of hepatic stellate cells (HSC) and proliferation of hepatocytes upon liver injury. HCC is frequently associated with overexpression of the proto-oncogene c-myc. However, the impact of c-myc for initiating pathological precursor stages such as liver fibrosis is poorly characterized. In the present study we thus investigated the impact of c-myc for liver fibrogenesis.MethodsExpression of c-myc was measured in biopsies of patients with liver fibrosis of different etiologies by quantitative real-time PCR (qPCR). Primary HSC were isolated from mice with transgenic overexpression of c-myc in hepatocytes (alb-myc^tg) and wildtype (WT) controls and investigated for markers of cell cycle progression and fibrosis by qPCR and immunofluorescence microscopy. Liver fibrosis in WT and alb-myc^tg mice was induced by repetitive CCl₄ treatment.ResultsWe detected strong up-regulation of hepatic c-myc in patients with advanced liver fibrosis. In return, overexpression of c-myc in alb-myc^tg mice resulted in increased liver collagen deposition and induction of α-smooth-muscle-actin indicating HSC activation. Primary HSC derived from alb-myc^tg mice showed enhanced proliferation and accelerated transdifferentiation into myofibroblasts in vitro. Accordingly, fibrosis initiation in vivo after chronic CCl₄ treatment was accelerated in alb-myc^tg mice compared to controls.ConclusionOverexpression of c-myc is a novel marker of liver fibrosis in man and mice. We conclude that chronic induction of c-myc especially in hepatocytes has the potential to prime resident HSC for activation, proliferation and myofibroblast differentiation.     

Endoglin in liver fibrosis

Liver fibrosis occurs in most types of chronic liver diseases and is characterized by excessive accumulation of extracellular matrix proteins, leading to disruption of tissue function and eventually organ failure. Transforming growth factor (TGF)-β represents an important pro-fibrogenic factor and aberrant TGF-β action has been implicated in many disease processes of the liver. Endoglin is a TGF-β co-receptor expressed mainly in endothelial cells that has been shown to differentially regulates TGF-β signal transduction by inhibiting ALK5-Smad2/3 signalling and augmenting ALK1-Smad1/5 signalling. Recent reports demonstrating upregulation of endoglin expression in pro-fibrogenic cell types such as scleroderma fibroblasts and hepatic stellate cells have led to studies exploring the potential involvement of this TGF-β co-receptor in organ fibrosis. A recent article by Meurer and colleagues now shows that endoglin expression is increased in transdifferentiating hepatic stellate cells in vitro and in two different models (carbon tetrachloride intoxication and bile duct ligation) of liver fibrosis in vivo. Moreover, they show that endoglin overexpression in hepatic stellate cells is associated with enhanced TGF-β-driven Smad1/5 phosphorylation and α-smooth muscle actin production without altering Smad2/3 signaling. These findings suggest that endoglin may play an important role in hepatic fibrosis by altering the balance of TGF-β signaling via the ALK1-Smad1/5 and ALK-Smad2/3 pathways and raise the possibility that targeting endoglin expression in transdifferentiating hepatic stellate cells may represent a novel therapeutic strategy for the treatment of liver fibrosis.