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Extracellular Matrix

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Signaling Pathways in Liver Diseases

Abstract

The hepatic extracellular matrix (ECM) is a complex network of macromolecules that not only provides cells with an extracellular scaffold but also plays an important role in the regulation of cellular activities [1, 2]. In a normal liver, the ECM comprises less than 3% of the relative area on a tissue section and approximately 0.5% of the wet weight [3]. In addition to Glisson’s capsule, ECM is found mainly in the portal tracts and the central veins. Small amounts of ECM, the perisinusoidal matrix, are also found in the subendothelial space of Disse. The sinusoids are lined by fenestrated endothelial cells which lack an electron-dense basement membrane (BM), which facilitates the bidirectional flow of plasma between sinusoidal lumen and the hepatocytes. The strategic position of the perisinusoidal matrix at the interface between blood and the epithelial components of the liver explains why quantitative or qualitative change of ECM may significantly influence hepatic function [4]. Greater understanding of the structure and function of the ECM in the liver is vital not only for defining new therapeutic targets, but also for replicating functions of liver ex vivo using tissue engineering approaches in the hope of developing liver assist devices [5–7].

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References

  1. Schuppan D et al (2001) Matrix as modulator of stellate cell and hepatic fibrogenesis. Semin Liver Dis 21(3):351–372

    Article  PubMed  CAS  Google Scholar 

  2. Marastoni S et al (2008) Extracellular matrix: a matter of life and death. Connect Tissue Res 49(3):203–206

    Article  PubMed  CAS  Google Scholar 

  3. Geerts A (2001) History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells. Semin Liver Dis 21(3):311–335

    Article  PubMed  CAS  Google Scholar 

  4. Bedossa P, Paradis V (2003) Liver extracellular matrix in health and disease. J Pathol 200(4):504–515

    Article  PubMed  Google Scholar 

  5. Flaim CJ, Chien S, Bhatia SN (2005) An extracellular matrix microarray for probing cellular differentiation. Nat Methods 2(2):119–125

    Article  PubMed  CAS  Google Scholar 

  6. Liu Tsang V et al (2007) Fabrication of 3D hepatic tissues by additive photopatterning of cellular hydrogels. FASEB J 21(3):790–801

    Article  PubMed  CAS  Google Scholar 

  7. Griffith LG, Swartz MA (2006) Capturing complex 3D tissue physiology in vitro. Nat Rev Mol Cell Biol 7(3): 211–224

    Article  PubMed  CAS  Google Scholar 

  8. Maylin S et al (2008) Eradication of hepatitis C virus in patients successfully treated for chronic hepatitis C. Gastroenterology 135(3):821–829

    Article  PubMed  Google Scholar 

  9. Mallet V et al (2008) Brief communication: the relationship of regression of cirrhosis to outcome in chronic hepatitis C. Ann Intern Med 149(6):399–403

    PubMed  Google Scholar 

  10. Friedman SL, Bansal MB (2006) Reversal of hepatic fibro­sis – fact or fantasy? Hepatology 43(2 Suppl 1):S82–S88

    Article  CAS  Google Scholar 

  11. Guo J, Friedman SL (2007) Hepatic fibrogenesis. Semin Liver Dis 27(4):413–426

    Article  PubMed  CAS  Google Scholar 

  12. Friedman SL (2008) Hepatic stellate cells–protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 88(1):125–172

    Article  PubMed  CAS  Google Scholar 

  13. Friedman SL (2008) Mechanisms of hepatic fibrogenesis. Gastroenterology 134(6):1655–1669

    Article  PubMed  CAS  Google Scholar 

  14. Schuppan D, Afdhal NH (2008) Liver cirrhosis. Lancet 371(9615):838–851

    Article  PubMed  CAS  Google Scholar 

  15. Wells RG (2008) The role of matrix stiffness in regulating cell behavior. Hepatology 47(4):1394–1400

    Article  PubMed  CAS  Google Scholar 

  16. Wong GL et al (2008) Assessment of fibrosis by transient elastography compared with liver biopsy and morphometry in chronic liver diseases. Clin Gastroenterol Hepatol 6(9): 1027–1035

    Article  PubMed  Google Scholar 

  17. Kettaneh A et al (2007) Features associated with success rate and performance of fibroscan measurements for the diagnosis of cirrhosis in HCV patients: a prospective study of 935 patients. J Hepatol 46(4):628–634

    Article  PubMed  Google Scholar 

  18. Castera L et al (2005) Prospective comparison of transient elastography, fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology 128(2):343–350

    Article  PubMed  Google Scholar 

  19. Talwalkar JA et al (2008) Magnetic resonance imaging of hepatic fibrosis: emerging clinical applications. Hepatology 47(1):332–342

    Article  PubMed  Google Scholar 

  20. Arena U et al (2008) Acute viral hepatitis increases liver stiffness values measured by transient elastography. Hepatology 47(2):380–384

    Article  PubMed  CAS  Google Scholar 

  21. Coco B et al (2007) Transient elastography: a new surrogate marker of liver fibrosis influenced by major changes of transaminases. J Viral Hepat 14(5):360–369

    Article  PubMed  CAS  Google Scholar 

  22. Kavitha O, Thampan RV (2008) Factors influencing collagen biosynthesis. J Cell Biochem 104(4):1150–1160

    Article  PubMed  CAS  Google Scholar 

  23. Kadler KE, Hill A, Canty-Laird EG (2008) Collagen fibrillogenesis: fibronectin, integrins, and minor collagens as organizers and nucleators. Curr Opin Cell Biol 20(5):495–501

    Article  PubMed  CAS  Google Scholar 

  24. Zhu ZW et al (2001) Enhanced glypican-3 expression differentiates the majority of hepatocellular carcinomas from benign hepatic disorders. Gut 48(4):558–564

    Article  PubMed  CAS  Google Scholar 

  25. Bosman FT, Stamenkovic I (2003) Functional structure and composition of the extracellular matrix. J Pathol 200(4): 423–428

    Article  PubMed  CAS  Google Scholar 

  26. Jarnagin WR et al (1994) Expression of variant fibronectins in wound healing: cellular source and biological activity of the EIIIA segment in rat hepatic fibrogenesis. J Cell Biol 127(6 Pt 2):2037–2048

    Article  PubMed  CAS  Google Scholar 

  27. Bornstein P (2002) Cell–matrix interactions: the view from the outside. Methods Cell Biol 69:7–11

    Article  PubMed  CAS  Google Scholar 

  28. Bornstein P, Sage EH (2002) Matricellular proteins: extracellular modulators of cell function. Curr Opin Cell Biol 14(5):608–616

    Article  PubMed  CAS  Google Scholar 

  29. Frizell E et al (1995) Expression of SPARC in normal and fibrotic livers. Hepatology 21(3):847–854

    PubMed  CAS  Google Scholar 

  30. Nakatani K et al (2002) Expression of SPARC by activated hepatic stellate cells and its correlation with the stages of fibrogenesis in human chronic hepatitis. Virchows Arch 441(5):466–474

    Article  PubMed  CAS  Google Scholar 

  31. Tokairin T et al (2008) Osteopontin expression in the liver with severe perisinusoidal fibrosis: autopsy case of Down syndrome with transient myeloproliferative disorder. Pathol Int 58(1):64–68

    Article  PubMed  Google Scholar 

  32. El-Karef A et al (2007) Expression of large tenascin-C splice variants by hepatic stellate cells/myofibroblasts in chronic hepatitis C. J Hepatol 46(4):664–673

    Article  PubMed  CAS  Google Scholar 

  33. Lee SH et al (2004) Effects and regulation of osteopontin in rat hepatic stellate cells. Biochem Pharmacol 68(12): 2367–2378

    Article  PubMed  CAS  Google Scholar 

  34. Rojkind M, Giambrone MA, Biempica L (1979) Collagen types in normal and cirrhotic liver. Gastroenterology 76(4):710–719

    PubMed  CAS  Google Scholar 

  35. Hahn E et al (1980) Distribution of basement membrane proteins in normal and fibrotic human liver: collagen type IV, laminin, and fibronectin. Gut 21(1):63–71

    Article  PubMed  CAS  Google Scholar 

  36. Gressner AM, Bachem MG (1990) Cellular sources of noncollagenous matrix proteins: role of fat-storing cells in fibrogenesis. Semin Liver Dis 10(1):30–46

    Article  PubMed  CAS  Google Scholar 

  37. McGuire RF et al (1992) Role of extracellular matrix in regulating fenestrations of sinusoidal endothelial cells isolated from normal rat liver. Hepatology 15(6):989–997

    Article  PubMed  CAS  Google Scholar 

  38. Friedman SL et al (1989) Maintenance of differentiated phenotype of cultured rat hepatic lipocytes by basement membrane matrix. J Biol Chem 264(18):10756–10762

    PubMed  CAS  Google Scholar 

  39. Sohara N et al (2002) Reversal of activation of human myofibroblast-like cells by culture on a basement membrane-like substrate. J Hepatol 37(2):214–221

    Article  PubMed  CAS  Google Scholar 

  40. Gaca MD et al (2003) Basement membrane-like matrix inhibits proliferation and collagen synthesis by activated rat hepatic stellate cells: evidence for matrix-dependent deactivation of stellate cells. Matrix Biol 22(3): 229–239

    Article  PubMed  CAS  Google Scholar 

  41. Han YP et al (2007) A matrix metalloproteinase-9 activation cascade by hepatic stellate cells in trans-differentiation in the three-dimensional extracellular matrix. J Biol Chem 282(17):12928–12939

    Article  PubMed  CAS  Google Scholar 

  42. Somasundaram R, Schuppan D (1996) Type I, II, III, IV, V, and VI collagens serve as extracellular ligands for the isoforms of platelet-derived growth factor (AA, BB, and AB). J Biol Chem 271(43):26884–26891

    Article  PubMed  CAS  Google Scholar 

  43. Berrier AL, Yamada KM (2007) Cell–matrix adhesion. J Cell Physiol 213(3):565–573

    Article  PubMed  CAS  Google Scholar 

  44. Lock JG, Wehrle-Haller B, Stromblad S (2008) Cell–matrix adhesion complexes: master control machinery of cell migration. Semin Cancer Biol 18(1):65–76

    Article  PubMed  CAS  Google Scholar 

  45. Danen EH (2005) Integrins: regulators of tissue function and cancer progression. Curr Pharm Des 11(7):881–891

    Article  PubMed  CAS  Google Scholar 

  46. McCall-Culbreath KD, Zutter MM (2008) Collagen receptor integrins: rising to the challenge. Curr Drug Targets 9(2): 139–149

    Article  PubMed  CAS  Google Scholar 

  47. Avraamides CJ, Garmy-Susini B, Varner JA (2008) Integrins in angiogenesis and lymphangiogenesis. Nat Rev Cancer 8(8):604–617

    Article  PubMed  CAS  Google Scholar 

  48. Silva R et al (2008) Integrins: the keys to unlocking angiogenesis. Arterioscler Thromb Vasc Biol 28(10):1703–1713

    Article  PubMed  CAS  Google Scholar 

  49. Xiong JP, Goodman SL, Arnaout MA (2007) Purification, analysis, and crystal structure of integrins. Methods Enzymol 426:307–336

    Article  PubMed  CAS  Google Scholar 

  50. Stupack DG (2007) The biology of integrins. Oncology 21(9 Suppl 3):6–12

    PubMed  Google Scholar 

  51. Lelievre SA et al (1998) Tissue phenotype depends on reciprocal interactions between the extracellular matrix and the structural organization of the nucleus. Proc Natl Acad Sci U S A 95(25):14711–14716

    Article  PubMed  CAS  Google Scholar 

  52. Shafiei MS, Rockey DC (2006) The role of integrin-linked kinase in liver wound healing. J Biol Chem 281(34): 24863–24872

    Article  PubMed  CAS  Google Scholar 

  53. Melton AC et al (2007) Focal adhesion disassembly is an essential early event in hepatic stellate cell chemotaxis. Am J Physiol Gastrointest Liver Physiol 293(6):G1272–G1280

    Article  CAS  Google Scholar 

  54. Carloni V et al (2000) Tyrosine phosphorylation of focal adhesion kinase by PDGF is dependent on ras in human hepatic stellate cells. Hepatology 31(1):131–140

    Article  PubMed  CAS  Google Scholar 

  55. Carloni V et al (1996) Expression and function of integrin receptors for collagen and laminin in cultured human hepatic stellate cells. Gastroenterology 110(4):1127–1136

    Article  PubMed  CAS  Google Scholar 

  56. Pinzani M, Marra F, Carloni V (1998) Signal transduction in hepatic stellate cells. Liver 18:2–13

    PubMed  CAS  Google Scholar 

  57. Levine D et al (2000) Expression of the integrin α8β1 during pulmonary and hepatic fibrosis. Am J Pathol 156(6):1927–1935

    PubMed  CAS  Google Scholar 

  58. Znoyko I, Trojanowska M, Reuben A (2006) Collagen binding α2β1 and α1β1 integrins play contrasting roles in regulation of Ets-1 expression in human liver myofibroblasts. Mol Cell Biochem 282(1–2):89–99

    Article  PubMed  CAS  Google Scholar 

  59. Patsenker E et al (2007) Pharmacological inhibition of the vitronectin receptor abrogates PDGF-BB-induced hepatic stellate cell migration and activation in vitro. J Hepatol 46(5):878–887

    Article  PubMed  CAS  Google Scholar 

  60. Wang B et al (2007) Role of αvβ6 integrin in acute biliary fibrosis. Hepatology 46(5):1404–1412

    Article  PubMed  CAS  Google Scholar 

  61. Popov Y et al (2008) Integrin αvβ6 is a marker of the progression of biliary and portal liver fibrosis and a novel target for antifibrotic therapies. J Hepatol 48(3):453–464

    Article  PubMed  CAS  Google Scholar 

  62. Patsenker E et al (2008) Inhibition of integrin αvβ6 on cholangiocytes blocks transforming growth factor-β activation and retards biliary fibrosis progression. Gastroenterology 135(2):660–670

    Article  PubMed  CAS  Google Scholar 

  63. Munger JS et al (1999) The integrin αvβ6 binds and activates latent TGF β1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 96(3):319–328

    Article  PubMed  CAS  Google Scholar 

  64. Omenetti A et al (2008) Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans. J Clin Invest 118(10):3331–3342

    PubMed  CAS  Google Scholar 

  65. Omenetti A et al (2008) The hedgehog pathway regulates remodelling responses to biliary obstruction in rats. Gut 57(9):1275–1282

    Article  PubMed  CAS  Google Scholar 

  66. Hehlgans S, Haase M, Cordes N (2007) Signalling via integrins: implications for cell survival and anticancer strategies. Biochim Biophys Acta 1775(1):163–180

    PubMed  CAS  Google Scholar 

  67. Primakoff P, Myles DG (2000) The ADAM gene family: surface proteins with adhesion and protease activity. Trends Genet 16(2):83–87

    Article  PubMed  CAS  Google Scholar 

  68. Kesteloot F et al (2007) ADAM metallopeptidase with thrombospondin type 1 motif 2 inactivation reduces the extent and stability of carbon tetrachloride-induced hepatic fibrosis in mice. Hepatology 46(5):1620–1631

    Article  PubMed  CAS  Google Scholar 

  69. Diamantis I et al (2000) Cloning of the rat ADAMTS-1 gene and its down regulation in endothelial cells in cirrhotic rats. Liver 20(2):165–172

    Article  PubMed  CAS  Google Scholar 

  70. Zhou W et al (2005) ADAMTS13 is expressed in hepatic stellate cells. Lab Invest 85(6):780–788

    Article  PubMed  CAS  Google Scholar 

  71. Niiya M et al (2006) Increased ADAMTS-13 proteolytic activity in rat hepatic stellate cells upon activation in vitro and in vivo. J Thromb Haemost 4(5):1063–1070

    Article  PubMed  CAS  Google Scholar 

  72. Bourd-Boittin K et al (2008) RACK1, a new ADAM12 interacting protein. Contribution to liver fibrogenesis. J Biol Chem 283(38):26000–26009

    Article  PubMed  CAS  Google Scholar 

  73. Labrador JP et al (2001) The collagen receptor DDR2 regulates proliferation and its elimination leads to dwarfism. EMBO Rep 2(5):446–452

    PubMed  CAS  Google Scholar 

  74. Olaso E et al (2001) DDR2 receptor promotes MMP-2-mediated proliferation and invasion by hepatic stellate cells. J Clin Invest 108(9):1369–1378

    PubMed  CAS  Google Scholar 

  75. Mao TK et al (2002) Elevated expression of tyrosine kinase DDR2 in primary biliary cirrhosis. Autoimmunity 35(8): 521–529

    Article  PubMed  CAS  Google Scholar 

  76. Maeyama M et al (2008) Switching in discoid domain receptor expressions in SLUG-induced epithelial–mesenchymal transition. Cancer 113(10):2823–2831

    Article  PubMed  CAS  Google Scholar 

  77. Gressner OA, Gressner AM (2008) Connective tissue growth factor: a fibrogenic master switch in fibrotic liver diseases. Liver Int 28(8):1065–1079

    Article  PubMed  CAS  Google Scholar 

  78. Yoshiji H et al (2003) Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis. Gut 52(9):1347–1354

    Article  PubMed  CAS  Google Scholar 

  79. Asano Y et al (2007) Hepatocyte growth factor promotes remodeling of murine liver fibrosis, accelerating recruitment of bone marrow-derived cells into the liver. Hepatol Res 37(12):1080–1094

    Article  PubMed  Google Scholar 

  80. Roskams T (2006) Different types of liver progenitor cells and their niches. J Hepatol 45(1):1–4

    Article  PubMed  Google Scholar 

  81. Roskams T (2008) Relationships among stellate cell activation, progenitor cells, and hepatic regeneration. Clin Liver Dis 12(4):853–860; ix

    Google Scholar 

  82. Kordes C et al (2007) CD133+ hepatic stellate cells are progenitor cells. Biochem Biophys Res Commun 352(2):410–417

    Article  PubMed  CAS  Google Scholar 

  83. Kubota H, Yao HL, Reid LM (2007) Identification and ­characterization of vitamin A-storing cells in fetal liver: implications for functional importance of hepatic stellate cells in liver development and hematopoiesis. Stem Cells 25(9): 2339–2349

    Article  PubMed  CAS  Google Scholar 

  84. Pi L et al (2008) Connective tissue growth factor with a novel fibronectin binding site promotes cell adhesion and migration during rat oval cell activation. Hepatology 47(3): 996–1004

    Article  PubMed  CAS  Google Scholar 

  85. Benyon RC, Arthur MJ (2001) Extracellular matrix degradation and the role of hepatic stellate cells. Semin Liver Dis 21(3):373–384

    Article  PubMed  CAS  Google Scholar 

  86. Han YP (2006) Matrix metalloproteinases, the pros and cons, in liver fibrosis. J Gastroenterol Hepatol 21(Suppl 3):S88–S91

    Article  CAS  Google Scholar 

  87. Iredale JP (2001) Hepatic stellate cell behavior during resolution of liver injury. Semin Liver Dis 21(3):427–436

    Article  PubMed  CAS  Google Scholar 

  88. Iredale JP (2007) Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. J Clin Invest 117(3):539–548

    Article  PubMed  CAS  Google Scholar 

  89. Duffield JS et al (2005) Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest 115(1):56–65

    PubMed  CAS  Google Scholar 

  90. Fallowfield JA et al (2007) Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J Immunol 178(8):5288–5295

    PubMed  CAS  Google Scholar 

  91. Lee JS et al (2007) Sinusoidal remodeling and angiogenesis: a new function for the liver-specific pericyte? Hepatology 45(3):817–825

    Article  PubMed  CAS  Google Scholar 

  92. Semela D et al (2008) Platelet-derived growth factor signaling through ephrin-b2 regulates hepatic vascular structure and function. Gastroenterology 135(2): 671–679

    Article  PubMed  CAS  Google Scholar 

  93. Taura K et al (2008) Hepatic stellate cells secrete angiopoietin 1 that induces angiogenesis in liver fibrosis. Gastroenterology 135(5):1729–1738

    Article  PubMed  CAS  Google Scholar 

  94. Yang L et al (2008) Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells. J Hepatol 48(1):98–106

    Article  PubMed  CAS  Google Scholar 

  95. Friedman SL, Millward-Sadler H, Arthur MJP (1992) Liver fibrosis and cirrhosis. Wright’s liver and biliary disease, 3rd edn. WB Saunders, London

    Google Scholar 

  96. Friedman SL, Arthur MJP (2002) Reversing hepatic fibrosis. Sci Med 8(4):194–205

    CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Liver Diseases, Mount Sinai School of Medicine, 1425 Madison Avenue, 1123, New York, NY, 10029-6574, USA

    Scott L. Friedman

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  1. Inselspital, Universität Bern, Murtenstr. 35, Bern, 3010, Switzerland

    Jean-Francois Dufour

  2. Klinik für Viszeral- und, Universitätsspital Zürich, Rämistr. 100, Zürich, 8091, Switzerland

    Pierre-Alain Clavien

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Friedman, S.L. (2010). Extracellular Matrix. In: Dufour, JF., Clavien, PA. (eds) Signaling Pathways in Liver Diseases. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-00150-5_6

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  • DOI: https://doi.org/10.1007/978-3-642-00150-5_6

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