Liver precursor cells increase hepatic fibrosis induced by chronic carbon tetrachloride intoxication in rats.

Hepatic fibrosis, the major complication of virtually all types of chronic liver damage, usually begins in portal areas, and its severity has been correlated to liver progenitor cells (LPC) expansion from periportal areas, even if the primary targets of injury are intralobular hepatocytes. The aim of this study was to determine the potential fibrogenic role of LPC, using a new experimental model in which rat liver fibrosis was induced by chronic carbon tetrachloride (CCl(4)) administration for 6 weeks, in combination with chronic acetylaminofluorene treatment (AAF), which promotes activation of LPC compartment. Treatment with CCl(4) alone caused a significant increase in serum transaminase activity as well as liver fibrosis initiating around central veins and leading to formation of incomplete centro-central septa with sparse fibrogenic cells expressing α-smooth muscle actin (αSMA).

Gas6 deficiency prevents liver inflammation, steatohepatitis, and fibrosis in mice.

The Gas6/Axl pathway has been increasingly implicated in regeneration and tissue repair and, recently, in the control of innate immunity. In liver, we have demonstrated that Gas6 and its receptor Axl are expressed in macrophages, progenitor cells, and myofibroblasts and that Gas6 deficiency reduced inflammation and myofibroblast activation, causing delayed liver repair in response to acute injury. All these data suggest a role of Gas6/Axl signaling in pathogenesis of chronic liver diseases.

Growth arrest-specific protein 6 deficiency impairs liver tissue repair after acute toxic hepatitis in mice.

Background/aims: Resident macrophages and myofibroblasts derived from hepatic stellate cells play a key role in liver wound healing. We previously reported that these sinusoidal cells secrete the growth arrest-specific protein 6 (Gas6) and express Axl, one of its receptors. Here we address the role of Gas6 in the healing process during acute liver injury.

Expression of matrix metalloproteinase-2 and -9 and of tissue inhibitor of matrix metalloproteinase-1 in liver regeneration from oval cells in rat.

Oval cells participate in liver regeneration when hepatocyte replication is impaired. These precursor cells proliferate in periportal regions and organize in ductules. They are surrounded by a basement membrane, the degradation of which by matrix metalloproteinases (MMP) might trigger their terminal differentiation into hepatocytes.

Induction of Gas6 protein in CCl4-induced rat liver injury and anti-apoptotic effect on hepatic stellate cells.

The protein product of the growth arrest-specific gene 6 (Gas6) is a secreted ligand for tyrosine kinase receptors, among which Axl is the most widely distributed and displays the highest affinity for Gas6. The Gas6/Axl signaling pathway has been increasingly implicated in growth and survival processes occurring during development and tissue repair. In liver, after an acute or chronic injury, repair involves macrophages and hepatic stellate cells (HSC) activated into myofibroblastic cells (HSC/MFB), which produce cytokines and matrix proteins.

Expression and role of Gas6 protein and of its receptor Axl in hepatic regeneration from oval cells in the rat.

Background & Aims: The growth arrest-specific gene 6 (Gas6) protein is a vitamin K-dependent protein that binds to the Axl subfamily of tyrosine kinase receptors and exerts antiapoptotic and proliferative effects. Because Gas6 plays a role in development and tissue remodelling, we studied its expression as well as that of its high-affinity receptor Axl in a well-characterized model of hepatic regeneration from precursor oval cells.

Methods: Hepatic regeneration was induced by treating rats with acetylaminofluorene followed by partial hepatectomy.

Expression of stromal cell-derived factor-1 and of its receptor CXCR4 in liver regeneration from oval cells in rat.

Stromal cell-derived factor-1 is a chemokine that plays a major role during embryogenesis. Since stromal cell-derived factor-1 and its unique receptor CXCR4 are involved in the differentiation of progenitor cells, we studied the expression of this chemokine and of its receptor in hepatic regeneration from precursor oval cells. Hepatic regeneration was induced by treating rats with 2-acetylaminofluorene, and followed by partial hepatectomy.

Apoptosis of human hepatic myofibroblasts promotes activation of matrix metalloproteinase-2.

Liver fibrosis is potentially reversible after removal of the injurious agent. Fibrosis resolution is characterized by apoptosis of hepatic myofibroblasts and degradation of extracellular matrix components. Matrix metalloproteinase-2 (MMP-2) is involved in matrix remodeling.

Matrix metalloproteinase-2 activation in human hepatic fibrosis regulation by cell-matrix interactions.

Matrix metalloproteinase-2 (MMP-2) is involved in extracellular matrix remodeling. It is secreted as a proenzyme and activated by membrane type-MMPs (MT-MMP), such as MT1-MMP. In liver fibrosis, MMP-2 is highly expressed in myofibroblasts and may have a profibrogenic role.

Platelet-derived growth factor-BB and thrombin generate positive and negative signals for human hepatic stellate cell proliferation. Role of a prostaglandin/cyclic AMP pathway and cross-talk with endothelin receptors.

Proliferation of myofibroblastic hepatic stellate cells (HSC) in response to growth factors is essential for the development of liver fibrosis. We have reported that prostaglandins (PG) and cyclic AMP (cAMP) inhibit growth of human HSC. This PG/cAMP pathway transduces the endothelin (ET) B-mediated antiproliferative effect of endothelin-1 (ET-1) and up-regulates ETB receptors.

Myofibroblasts and hepatocellular carcinoma: an in vivo and in vitro study.

Background/aims: The number of perisinusoidal myofibroblasts has been shown to be increased in hepatocellular carcinoma, as compared to cirrhosis. This increase might suggest a cooperative relationship between tumour cells and myofibroblasts. To assess this relationship, we undertook: (a) an immunohistochemical study to confirm the existence of an increased number of perisinusoidal myofibroblasts in human hepatocellular carcinoma, as compared to cirrhosis with or without liver cell dysplasia, (b) an in vitro study testing the role of normal or tumoral human hepatocytes in myofibroblast proliferation.

Pentoxifylline inhibits growth and collagen synthesis of cultured human hepatic myofibroblast-like cells.

During the course of liver fibrogenesis, myofibroblast-like cells (MFLC), mostly derived from hepatic stellate cells, proliferate and synthesize excessive amounts of extracellular matrix components. Pentoxifylline (PTX) elicits antiproliferative and antifibrogenic effects in human dermal fibroblasts. The aim of this study was to test the effects of PTX on the proliferation and the synthesis of collagen and gelatinase A in cultured human hepatic MFLC.

Growth inhibitory properties of endothelin-1 in activated human hepatic stellate cells: a cyclic adenosine monophosphate-mediated pathway. Inhibition of both extracellular signal-regulated kinase and c-Jun kinase and upregulation of endothelin B receptors.

During chronic liver diseases, hepatic stellate cells (HSC) acquire an activated myofibroblast-like phenotype, proliferate, and synthetize fibrosis components. We have shown that endothelin-1 (ET-1) inhibits the proliferation of activated human HSC via endothelin B (ETB) receptors. We now investigate the transduction pathway involved in the growth inhibitory effect of ET-1 in activated HSC.

Fibroblast growth factor 2 and transforming growth factor beta 1 interactions in human liver myofibroblasts.

Background & Aims: During liver fibrogenesis, myofibroblastic liver cells proliferate and synthesize components of fibrosis. Fibroblast growth factor 2 (FGF-2) is expressed in vivo in myofibroblastic liver cells (MFLCs) during fibrogenesis, and exogenous FGF-2 is mitogenic for MFLCs. The aim of this study was to study the expression and role of endogenous FGF-2 in cultured human MFLCs.

Human myofibroblastlike cells obtained by outgrowth are representative of the fibrogenic cells in the liver.

During human fibrogenesis, myofibroblastlike cells proliferate and are the main source of fibrosis components. We have used cultured myofibroblastlike cells obtained by outgrowth from explants of human liver to study the expression of extracellular matrix (ECM) components and matrix-metalloproteinase-2 (MMP-2) These cells contained types I, III, IV, and V procollagen messenger RNAs (mRNAs). They also expressed mRNAs for laminin B1 chain and for cellular and plasma fibronectin.

Growth inhibitory properties of endothelin-1 in human hepatic myofibroblastic Ito cells. An endothelin B receptor-mediated pathway.

Ito cells play a pivotal role in the development of liver fibrosis associated with chronic liver diseases. During this process, Ito cells acquire myofibroblastic features, proliferate, and synthesize fibrosis components. Considering the reported mitogenic properties of endothelin-1 (ET-1), we investigated its effects on the proliferation of human Ito cells in their myofibroblastic phenotype.

Interferon alfa and gamma inhibit proliferation and collagen synthesis of human Ito cells in culture.

During the course of ongoing liver fibrogenesis, Ito cells acquire myofibroblastic features, proliferate, and synthesize increased amounts of extracellular matrix components. Interferon (IFN) alfa and IFN gamma have been shown to elicit antiproliferative and/or antifibrogenic effects in various cell cultures of mesenchymal origin. The aim of this study was to investigate the effects of IFN-alpha and IFN-gamma on cultured human myofibroblastic Ito cells (MFBIC) proliferation and collagen synthesis and secretion.

Antiproliferative effects of ET-1 in human liver Ito cells: an ETB- and a cyclic AMP-mediated pathway.

Ito cells play a key role in the development of liver fibrosis associated with chronic liver diseases. Both ETA (20%) and ETB (80%) receptors were identified in human Ito cells. ET-1 did not stimulate proliferation of Ito cells.

Vascular lesions of the liver in sickle cell disease. A clinicopathological study in 26 living patients.

Background: Hepatic lesions in sickle cell disease have been studied essentially in autopsy series. Previous reports on living patients are rare and concern a limited number of cases. The aim of the present study is to report the clinical, biochemical, and hepatic histological findings in 26 living patients with sickle cell disease and hepatobiliary disease.

Effect of simvastatin, an inhibitor of hydroxy-methylglutaryl coenzyme A reductase, on the growth of human Ito cells.

During hepatic fibrogenesis, Ito cells proliferate, acquire a myofibroblastlike phenotype and synthesize increased amounts of extracellular matrix components. In this study, we have assessed the effects of simvastatin, an inhibitor of hydroxy-methylglutaryl-coenzyme A reductase, on the growth of human myofibroblastlike Ito cells. Cells were grown from explants of normal human liver and characterized by a positive staining for desmin and smooth muscle alpha-actin.