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      Angiogenesis and Fibrogenesis in Chronic Liver Diseases

      , , ,

      Cellular and Molecular Gastroenterology and Hepatology

      Elsevier

      Hypoxia, Liver Angiogenesis, Liver Fibrogenesis, Myofibroblasts, Akt, protein kinase B, Ang-1, angiopoietin-1, ANGPTL3, angiopoietin-like-3 peptide, CCL2, chemokine ligand 2, CCR, chemokine receptor, CLD, chronic liver disease, eNOS, endothelial nitric oxide synthase, ET-1, endothelin 1, HCC, hepatocellular carcinoma, Hh, Hedgehog, HIF, hypoxia-inducible factor, HSC, hepatic stellate cell, HSC/MFs, myofibroblast-like cells from activated hepatic stellate cells, LSEC, liver sinusoidal endothelial cell, MF, myofibroblast, MP, microparticle, NAFLD, nonalcoholic fatty liver disease, NASH, nonalcoholic steatohepatitis, NO, nitric oxide, PDGF, platelet-derived growth factor, ROS, reactive oxygen species, α-SMA, α-smooth muscle actin, VEGF, vascular endothelial growth factor, VEGF-R2, vascular endothelial growth factor receptor type 2

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          Abstract

          Pathologic angiogenesis appears to be intrinsically associated with the fibrogenic progression of chronic liver diseases, which eventually leads to the development of cirrhosis and related complications, including hepatocellular carcinoma. Several laboratories have suggested that this association is relevant for chronic liver disease progression, with angiogenesis proposed to sustain fibrogenesis. This minireview offers a synthesis of relevant findings and opinions that have emerged in the last few years relating liver angiogenesis to fibrogenesis. We discuss liver angiogenesis in normal and pathophysiologic conditions with a focus on the role of hypoxia and hypoxia-inducible factors and assess the evidence supporting a clear relationship between angiogenesis and fibrogenesis. A section is dedicated to the critical interactions between liver sinusoidal endothelial cells and either quiescent hepatic stellate cells or myofibroblast-like stellate cells. Finally, we introduce the unusual, dual (profibrogenic and proangiogenic) role of hepatic myofibroblasts and emerging evidence supporting a role for specific mediators like vasohibin and microparticles and microvesicles.

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          Most cited references 76

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          Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis

          Summary Chemical or traumatic damage to the liver is frequently associated with aberrant healing(fibrosis) that overrides liver regeneration 1–5 . The mechanism by which hepatic niche cells differentially modulate regeneration and fibrosis during liver repair remains to be defined 6–8 . Hepatic vascular niche predominantly represented by liver sinusoidal endothelial cells (LSECs), deploys paracrine trophogens, known as angiocrine factors, to stimulate regeneration 9–15 . Nevertheless, it remains unknown how pro-regenerative angiocrine signals from LSECs is subverted to promote fibrosis 16,17 . Here, by combining inducible endothelial cell (EC)-specific mouse gene deletion strategy and complementary models of acute and chronic liver injury, we revealed that divergent angiocrine signals from LSECs elicit regeneration after immediateinjury and provoke fibrosis post chronic insult. The pro-fibrotic transition of vascular niche results from differential expression of stromal derived factor-1 (SDF-1) receptors, CXCR7 and CXCR4 18–21 in LSECs. After acute injury, CXCR7 upregulation in LSECs acts in conjunction with CXCR4 to induce transcription factor Id1, deploying pro-regenerative angiocrine factors and triggering regeneration. Inducible deletion of Cxcr7 in adult mouse LSECs (Cxcr7 iΔEC/iΔEC) impaired liver regeneration by diminishing Id1-mediated production of angiocrine factors 9–11 . By contrast, after chronic injury inflicted by iterative hepatotoxin (carbon tetrachloride) injection and bile duct ligation, constitutive FGFR1 signaling in LSECs counterbalanced CXCR7-dependent pro-regenerative response and augmented CXCR4 expression. This predominance of CXCR4 over CXCR7 expression shifted angiocrine response of LSECs, stimulating proliferation of desmin+hepatic stellate-like cells 22,23 and enforcing a pro-fibrotic vascular niche. EC-specific ablation of either Fgfr1 (Fgfr1 iΔEC/iΔEC) or Cxcr4 (Cxcr4 iΔEC/iΔEC) in mice restored pro-regenerative pathway and prevented FGFR1-mediated maladaptive subversion of angiocrine factors. Similarly, selective CXCR7 activation in LSECs abrogated fibrogenesis. Thus, we have demonstrated that in response to liver injury, differential recruitment of pro-regenerative CXCR7/Id1 versus pro-fibrotic FGFR1/CXCR4 angiocrine pathways in vascular niche balances regeneration and fibrosis. These results provide a therapeutic roadmap to achieve hepatic regeneration without provoking fibrosis 1,2,4 .
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            Fibrosis-dependent mechanisms of hepatocarcinogenesis.

            Hepatocellular carcinoma (HCC) is a rising worldwide cause of cancer mortality, making the elucidation of its underlying mechanisms an urgent priority. The liver is unique in its response to injury, simultaneously undergoing regeneration and fibrosis. HCC occurs in the context of these two divergent responses, leading to distinctive pathways of carcinogenesis. In this review we highlight pathways of liver tumorigenesis that depend on, or are enhanced by, fibrosis. Activated hepatic stellate cells drive fibrogenesis, changing the composition of the extracellular matrix. Matrix quantity and stiffness also increase, providing a reservoir for bound growth factors. In addition to promoting angiogenesis, these factors may enhance the survival of both preneoplastic hepatocytes and activated hepatic stellate cells. Fibrotic changes also modulate the activity of inflammatory cells in the liver, reducing the activity of natural killer and natural killer T cells that normally contribute to tumor surveillance. These pathways synergize with inflammatory signals, including telomerase reactivation and reactive oxygen species release, ultimately resulting in cancer. Clarifying fibrosis-dependent tumorigenic mechanisms will help rationalize antifibrotic therapies as a strategy to prevent and treat HCC. Copyright © 2012 American Association for the Study of Liver Diseases.
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              History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells.

              In 1876, von Kupffer described liver Sternzellen (star-shaped cells). The functions of these cells remained enigmatic for 75 years until Ito observed lipid-containing perisinusoidal cells in human liver. In 1971, Wake demonstrated that the Sternzellen of von Kupffer and the fat-storing cells described by Ito were identical. Wake also established that these cells were important sites of vitamin A storage. Soon thereafter, Kent and Popper demonstrated that the stellate cells were intimately linked to the pathogenesis of hepatic fibrosis. Since then, these cells have been studied in detail. Quiescent stellate cells represent 5-8% of the total number of liver cells. They play a cardinal role in storage and controlled release of retinoids. They control extracellular matrix (ECM) turnover in the space of Disse by secreting the correct amounts of a limited number of ECM molecules, and by releasing matrix metalloproteinases and their inhibitors. By virtue of their long cytoplasmic processes, quiescent stellate cells presumably contribute to the control of blood flow through the sinusoidal capillaries. They are important sources of paracrine, autocrine, juxtacrine, and chemoattractant factors that maintain homeostasis in the microenvironment of the hepatic sinusoid.
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                Author and article information

                Contributors
                Journal
                Cell Mol Gastroenterol Hepatol
                Cell Mol Gastroenterol Hepatol
                Cellular and Molecular Gastroenterology and Hepatology
                Elsevier
                2352-345X
                September 2015
                13 July 2015
                : 1
                : 5
                : 477-488
                Affiliations
                Unit of Experimental Medicine and Clinical Pathology, Department of Clinical and Biological Sciences, School of Medicine, University of Torino, Torino, Italy
                Author notes
                [] Correspondence Address correspondence to: Maurizio Parola, PhD, Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, School of Medicine, University of Torino, Corso Raffaello 30–10125 Torino, Italy. fax: + 39-011-6707753. maurizio.parola@ 123456unito.it
                Article
                S2352-345X(15)00123-X
                10.1016/j.jcmgh.2015.06.011
                5301407
                © 2015 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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