SerpinB3 Promotes Pro-fibrogenic Responses in Activated Hepatic Stellate Cells.

SerpinB3 is a hypoxia- and hypoxia-inducible factor-2α-dependent cystein protease inhibitor that is up-regulated in hepatocellular carcinoma and in parenchymal cells during chronic liver diseases (CLD). SerpinB3 up-regulation in CLD patients has been reported to correlate with the extent of liver fibrosis and the production of transforming growth factor-β1, but the actual role of SerpinB3 in hepatic fibrogenesis is still poorly characterized. In the present study we analyzed the pro-fibrogenic action of SerpinB3 in cell cultures and in two different murine models of liver fibrosis.

Hypoxia, hypoxia-inducible factors and fibrogenesis in chronic liver diseases.

Fibrogenic progression of chronic liver diseases (CLDs) towards the end-point of cirrhosis is currently regarded, whatever the aetiology, as a dynamic and highly integrated cellular response to chronic liver injury. Liver fibrogenesis (i.e.

The biphasic nature of hypoxia-induced directional migration of activated human hepatic stellate cells.

Liver fibrogenesis is sustained by pro-fibrogenic myofibroblast-like cells (MFs), mainly originating from activated hepatic stellate cells (HSC/MFs) or portal (myo)fibroblasts, and is favoured by hypoxia-dependent angiogenesis. Human HSC/MFs were reported to express vascular-endothelial growth factor (VEGF) and VEGF-receptor type 2 and to migrate under hypoxic conditions. This study was designed to investigate early and delayed signalling mechanisms involved in hypoxia-induced migration of human HSC/MFs.

Chronic exposure to agmatine results in the selection of agmatine-resistant hepatoma cells.

During our study of the cytostatic effect of agmatine, we were able to isolate an agmatine resistant clone from a parental hepatoma cell line, HTC. These cells, called Agres, had slower growth rate than the parental cells when cultured in normal medium. The modification in polyamine content induced by agmatine was much lower in these cells and ornithine decarboxylase, S-adenosylmethionine decarboxylase and spermidine/spermine acetyltransferase activities were much less affected.

Dissection of the biphasic nature of hypoxia-induced motogenic action in bone marrow-derived human mesenchymal stem cells.

Hypoxic conditions have been reported to facilitate preservation of undifferentiated mesenchymal stem cell (MSC) phenotype and positively affect their colony-forming potential, proliferation, and migration/mobilization. In this study, designed to dissect mechanisms underlying hypoxia-dependent migration of bone marrow-derived human MSC (hMSC), signal transduction, and molecular mechanisms were evaluated by integrating morphological, molecular, and cell biology techniques, including the wound healing assay (WHA) and modified Boyden's chamber assay (BCA) to monitor migration. Exposure of hMSCs to moderate hypoxia resulted in a significant increase of migration of hMSCs in both WHA (from 6 to 20 hours) and BCA (within 6 hours).

Intracellular reactive oxygen species are required for directional migration of resident and bone marrow-derived hepatic pro-fibrogenic cells.

Background & Aims: Liver fibrogenesis is sustained by myofibroblast-like cells originating from hepatic stellate cells (HSC/MFs), portal fibroblasts or bone marrow-derived cells, including mesenchymal stem cells (MSCs). Herein, we investigated the mechanistic role of intracellular generation of reactive oxygen species (ROS) and redox-sensitive signal transduction pathways in mediating chemotaxis, a critical profibrogenic response for human HSC/MFs and for MSC potentially engrafting chronically injured liver.

Methods: Intracellular generation of ROS and signal transduction pathways were evaluated by integrating morphological and molecular biology techniques.

Liver fibrosis: a dynamic and potentially reversible process.

In any chronic liver disease (CLDs), whatever the aetiology, reiteration of liver injury results in persisting inflammation and progressive fibrogenesis, with chronic activation of the wound healing response in CLDs, representing a major driving force for progressive accumulation of ECM components, eventually leading to liver cirrhosis. Cirrhosis is characterized by fibrous septa dividing the hepatic parenchyma into regenerative pseudo-lobules, as well as by extensive changes in vascular architecture, the development of portal hypertension and related complications. Liver fibrogenesis (i.

Epithelial-mesenchymal transition: from molecular mechanisms, redox regulation to implications in human health and disease.

Epithelial to mesenchymal transition (EMT) is a fundamental process, paradigmatic of the concept of cell plasticity, that leads epithelial cells to lose their polarization and specialized junctional structures, to undergo cytoskeleton reorganization, and to acquire morphological and functional features of mesenchymal-like cells. Although EMT has been originally described in embryonic development, where cell migration and tissue remodeling have a primary role in regulating morphogenesis in multicellular organisms, recent literature has provided evidence suggesting that the EMT process is a more general biological process that is also involved in several pathophysiological conditions, including cancer progression and organ fibrosis. This review offers first a comprehensive introduction to describe major relevant features of EMT, followed by sections dedicated on those signaling mechanisms that are known to regulate or affect the process, including the recently proposed role for oxidative stress and reactive oxygen species (ROS).

Angiogenesis and liver fibrogenesis.

Angiogenesis is a dynamic, hypoxia-stimulated and growth factor-dependent process, eventually leading to the formation of new vessels from pre-existing blood vessels. In the last decade experimental and clinical studies have described the occurrence of hepatic angiogenesis in a number of different pathophysiological conditions, including those involving inflammatory, fibrotic and ischemic features. In particular, the literature evidence indicates that hepatic angiogenesis is strictly associated with, and may even favour fibrogenic progression of chronic inflammatory liver diseases of different aetiology.

Redox mechanisms switch on hypoxia-dependent epithelial-mesenchymal transition in cancer cells.

Epithelial-mesenchymal transition (EMT) and hypoxia are considered as crucial events favouring invasion and metastasis of many cancer cells. In this study, different human neoplastic cell lines of epithelial origin were exposed to hypoxic conditions in order to investigate whether hypoxia per se may trigger EMT programme as well as to mechanistically elucidate signal transduction mechanisms involved. The following human cancer cell lines were used: HepG2 (from human hepatoblastoma), PANC-1 (from pancreatic carcinoma), HT-29 (from colon carcinoma) and MCF-7 (from breast carcinoma).