Extracellular Matrix

  • Scott L. FriedmanEmail author


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].


Liver Fibrosis Focal Adhesion Kinase Stellate Cell Hepatic Stellate Cell Magnetic Resonance Elastography 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Schuppan D et al (2001) Matrix as modulator of stellate cell and hepatic fibrogenesis. Semin Liver Dis 21(3):351–372CrossRefPubMedGoogle Scholar
  2. 2.
    Marastoni S et al (2008) Extracellular matrix: a matter of life and death. Connect Tissue Res 49(3):203–206CrossRefPubMedGoogle Scholar
  3. 3.
    Geerts A (2001) History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells. Semin Liver Dis 21(3):311–335CrossRefPubMedGoogle Scholar
  4. 4.
    Bedossa P, Paradis V (2003) Liver extracellular matrix in health and disease. J Pathol 200(4):504–515CrossRefPubMedGoogle Scholar
  5. 5.
    Flaim CJ, Chien S, Bhatia SN (2005) An extracellular matrix microarray for probing cellular differentiation. Nat Methods 2(2):119–125CrossRefPubMedGoogle Scholar
  6. 6.
    Liu Tsang V et al (2007) Fabrication of 3D hepatic tissues by additive photopatterning of cellular hydrogels. FASEB J 21(3):790–801CrossRefPubMedGoogle Scholar
  7. 7.
    Griffith LG, Swartz MA (2006) Capturing complex 3D tissue physiology in vitro. Nat Rev Mol Cell Biol 7(3): 211–224CrossRefPubMedGoogle Scholar
  8. 8.
    Maylin S et al (2008) Eradication of hepatitis C virus in patients successfully treated for chronic hepatitis C. Gastroenterology 135(3):821–829CrossRefPubMedGoogle Scholar
  9. 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):399–403PubMedGoogle Scholar
  10. 10.
    Friedman SL, Bansal MB (2006) Reversal of hepatic fibro­sis – fact or fantasy? Hepatology 43(2 Suppl 1):S82–S88CrossRefGoogle Scholar
  11. 11.
    Guo J, Friedman SL (2007) Hepatic fibrogenesis. Semin Liver Dis 27(4):413–426CrossRefPubMedGoogle Scholar
  12. 12.
    Friedman SL (2008) Hepatic stellate cells–protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 88(1):125–172CrossRefPubMedGoogle Scholar
  13. 13.
    Friedman SL (2008) Mechanisms of hepatic fibrogenesis. Gastroenterology 134(6):1655–1669CrossRefPubMedGoogle Scholar
  14. 14.
    Schuppan D, Afdhal NH (2008) Liver cirrhosis. Lancet 371(9615):838–851CrossRefPubMedGoogle Scholar
  15. 15.
    Wells RG (2008) The role of matrix stiffness in regulating cell behavior. Hepatology 47(4):1394–1400CrossRefPubMedGoogle Scholar
  16. 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): 1027–1035CrossRefPubMedGoogle Scholar
  17. 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):628–634CrossRefPubMedGoogle Scholar
  18. 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):343–350CrossRefPubMedGoogle Scholar
  19. 19.
    Talwalkar JA et al (2008) Magnetic resonance imaging of hepatic fibrosis: emerging clinical applications. Hepatology 47(1):332–342CrossRefPubMedGoogle Scholar
  20. 20.
    Arena U et al (2008) Acute viral hepatitis increases liver stiffness values measured by transient elastography. Hepatology 47(2):380–384CrossRefPubMedGoogle Scholar
  21. 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):360–369CrossRefPubMedGoogle Scholar
  22. 22.
    Kavitha O, Thampan RV (2008) Factors influencing collagen biosynthesis. J Cell Biochem 104(4):1150–1160CrossRefPubMedGoogle Scholar
  23. 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):495–501CrossRefPubMedGoogle Scholar
  24. 24.
    Zhu ZW et al (2001) Enhanced glypican-3 expression differentiates the majority of hepatocellular carcinomas from benign hepatic disorders. Gut 48(4):558–564CrossRefPubMedGoogle Scholar
  25. 25.
    Bosman FT, Stamenkovic I (2003) Functional structure and composition of the extracellular matrix. J Pathol 200(4): 423–428CrossRefPubMedGoogle Scholar
  26. 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):2037–2048CrossRefPubMedGoogle Scholar
  27. 27.
    Bornstein P (2002) Cell–matrix interactions: the view from the outside. Methods Cell Biol 69:7–11CrossRefPubMedGoogle Scholar
  28. 28.
    Bornstein P, Sage EH (2002) Matricellular proteins: extracellular modulators of cell function. Curr Opin Cell Biol 14(5):608–616CrossRefPubMedGoogle Scholar
  29. 29.
    Frizell E et al (1995) Expression of SPARC in normal and fibrotic livers. Hepatology 21(3):847–854PubMedGoogle Scholar
  30. 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):466–474CrossRefPubMedGoogle Scholar
  31. 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):64–68CrossRefPubMedGoogle Scholar
  32. 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):664–673CrossRefPubMedGoogle Scholar
  33. 33.
    Lee SH et al (2004) Effects and regulation of osteopontin in rat hepatic stellate cells. Biochem Pharmacol 68(12): 2367–2378CrossRefPubMedGoogle Scholar
  34. 34.
    Rojkind M, Giambrone MA, Biempica L (1979) Collagen types in normal and cirrhotic liver. Gastroenterology 76(4):710–719PubMedGoogle Scholar
  35. 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):63–71CrossRefPubMedGoogle Scholar
  36. 36.
    Gressner AM, Bachem MG (1990) Cellular sources of noncollagenous matrix proteins: role of fat-storing cells in fibrogenesis. Semin Liver Dis 10(1):30–46CrossRefPubMedGoogle Scholar
  37. 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):989–997CrossRefPubMedGoogle Scholar
  38. 38.
    Friedman SL et al (1989) Maintenance of differentiated phenotype of cultured rat hepatic lipocytes by basement membrane matrix. J Biol Chem 264(18):10756–10762PubMedGoogle Scholar
  39. 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):214–221CrossRefPubMedGoogle Scholar
  40. 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): 229–239CrossRefPubMedGoogle Scholar
  41. 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):12928–12939CrossRefPubMedGoogle Scholar
  42. 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):26884–26891CrossRefPubMedGoogle Scholar
  43. 43.
    Berrier AL, Yamada KM (2007) Cell–matrix adhesion. J Cell Physiol 213(3):565–573CrossRefPubMedGoogle Scholar
  44. 44.
    Lock JG, Wehrle-Haller B, Stromblad S (2008) Cell–matrix adhesion complexes: master control machinery of cell migration. Semin Cancer Biol 18(1):65–76CrossRefPubMedGoogle Scholar
  45. 45.
    Danen EH (2005) Integrins: regulators of tissue function and cancer progression. Curr Pharm Des 11(7):881–891CrossRefPubMedGoogle Scholar
  46. 46.
    McCall-Culbreath KD, Zutter MM (2008) Collagen receptor integrins: rising to the challenge. Curr Drug Targets 9(2): 139–149CrossRefPubMedGoogle Scholar
  47. 47.
    Avraamides CJ, Garmy-Susini B, Varner JA (2008) Integrins in angiogenesis and lymphangiogenesis. Nat Rev Cancer 8(8):604–617CrossRefPubMedGoogle Scholar
  48. 48.
    Silva R et al (2008) Integrins: the keys to unlocking angiogenesis. Arterioscler Thromb Vasc Biol 28(10):1703–1713CrossRefPubMedGoogle Scholar
  49. 49.
    Xiong JP, Goodman SL, Arnaout MA (2007) Purification, analysis, and crystal structure of integrins. Methods Enzymol 426:307–336CrossRefPubMedGoogle Scholar
  50. 50.
    Stupack DG (2007) The biology of integrins. Oncology 21(9 Suppl 3):6–12PubMedGoogle Scholar
  51. 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):14711–14716CrossRefPubMedGoogle Scholar
  52. 52.
    Shafiei MS, Rockey DC (2006) The role of integrin-linked kinase in liver wound healing. J Biol Chem 281(34): 24863–24872CrossRefPubMedGoogle Scholar
  53. 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–G1280CrossRefGoogle Scholar
  54. 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):131–140CrossRefPubMedGoogle Scholar
  55. 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):1127–1136CrossRefPubMedGoogle Scholar
  56. 56.
    Pinzani M, Marra F, Carloni V (1998) Signal transduction in hepatic stellate cells. Liver 18:2–13PubMedGoogle Scholar
  57. 57.
    Levine D et al (2000) Expression of the integrin α8β1 during pulmonary and hepatic fibrosis. Am J Pathol 156(6):1927–1935PubMedGoogle Scholar
  58. 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):89–99CrossRefPubMedGoogle Scholar
  59. 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):878–887CrossRefPubMedGoogle Scholar
  60. 60.
    Wang B et al (2007) Role of αvβ6 integrin in acute biliary fibrosis. Hepatology 46(5):1404–1412CrossRefPubMedGoogle Scholar
  61. 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):453–464CrossRefPubMedGoogle Scholar
  62. 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):660–670CrossRefPubMedGoogle Scholar
  63. 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):319–328CrossRefPubMedGoogle Scholar
  64. 64.
    Omenetti A et al (2008) Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans. J Clin Invest 118(10):3331–3342PubMedGoogle Scholar
  65. 65.
    Omenetti A et al (2008) The hedgehog pathway regulates remodelling responses to biliary obstruction in rats. Gut 57(9):1275–1282CrossRefPubMedGoogle Scholar
  66. 66.
    Hehlgans S, Haase M, Cordes N (2007) Signalling via integrins: implications for cell survival and anticancer strategies. Biochim Biophys Acta 1775(1):163–180PubMedGoogle Scholar
  67. 67.
    Primakoff P, Myles DG (2000) The ADAM gene family: surface proteins with adhesion and protease activity. Trends Genet 16(2):83–87CrossRefPubMedGoogle Scholar
  68. 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):1620–1631CrossRefPubMedGoogle Scholar
  69. 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):165–172CrossRefPubMedGoogle Scholar
  70. 70.
    Zhou W et al (2005) ADAMTS13 is expressed in hepatic stellate cells. Lab Invest 85(6):780–788CrossRefPubMedGoogle Scholar
  71. 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):1063–1070CrossRefPubMedGoogle Scholar
  72. 72.
    Bourd-Boittin K et al (2008) RACK1, a new ADAM12 interacting protein. Contribution to liver fibrogenesis. J Biol Chem 283(38):26000–26009CrossRefPubMedGoogle Scholar
  73. 73.
    Labrador JP et al (2001) The collagen receptor DDR2 regulates proliferation and its elimination leads to dwarfism. EMBO Rep 2(5):446–452PubMedGoogle Scholar
  74. 74.
    Olaso E et al (2001) DDR2 receptor promotes MMP-2-mediated proliferation and invasion by hepatic stellate cells. J Clin Invest 108(9):1369–1378PubMedGoogle Scholar
  75. 75.
    Mao TK et al (2002) Elevated expression of tyrosine kinase DDR2 in primary biliary cirrhosis. Autoimmunity 35(8): 521–529CrossRefPubMedGoogle Scholar
  76. 76.
    Maeyama M et al (2008) Switching in discoid domain receptor expressions in SLUG-induced epithelial–mesenchymal transition. Cancer 113(10):2823–2831CrossRefPubMedGoogle Scholar
  77. 77.
    Gressner OA, Gressner AM (2008) Connective tissue growth factor: a fibrogenic master switch in fibrotic liver diseases. Liver Int 28(8):1065–1079CrossRefPubMedGoogle Scholar
  78. 78.
    Yoshiji H et al (2003) Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis. Gut 52(9):1347–1354CrossRefPubMedGoogle Scholar
  79. 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):1080–1094CrossRefPubMedGoogle Scholar
  80. 80.
    Roskams T (2006) Different types of liver progenitor cells and their niches. J Hepatol 45(1):1–4CrossRefPubMedGoogle Scholar
  81. 81.
    Roskams T (2008) Relationships among stellate cell activation, progenitor cells, and hepatic regeneration. Clin Liver Dis 12(4):853–860; ixGoogle Scholar
  82. 82.
    Kordes C et al (2007) CD133+ hepatic stellate cells are progenitor cells. Biochem Biophys Res Commun 352(2):410–417CrossRefPubMedGoogle Scholar
  83. 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): 2339–2349CrossRefPubMedGoogle Scholar
  84. 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): 996–1004CrossRefPubMedGoogle Scholar
  85. 85.
    Benyon RC, Arthur MJ (2001) Extracellular matrix degradation and the role of hepatic stellate cells. Semin Liver Dis 21(3):373–384CrossRefPubMedGoogle Scholar
  86. 86.
    Han YP (2006) Matrix metalloproteinases, the pros and cons, in liver fibrosis. J Gastroenterol Hepatol 21(Suppl 3):S88–S91CrossRefGoogle Scholar
  87. 87.
    Iredale JP (2001) Hepatic stellate cell behavior during resolution of liver injury. Semin Liver Dis 21(3):427–436CrossRefPubMedGoogle Scholar
  88. 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):539–548CrossRefPubMedGoogle Scholar
  89. 89.
    Duffield JS et al (2005) Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest 115(1):56–65PubMedGoogle Scholar
  90. 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):5288–5295PubMedGoogle Scholar
  91. 91.
    Lee JS et al (2007) Sinusoidal remodeling and angiogenesis: a new function for the liver-specific pericyte? Hepatology 45(3):817–825CrossRefPubMedGoogle Scholar
  92. 92.
    Semela D et al (2008) Platelet-derived growth factor signaling through ephrin-b2 regulates hepatic vascular structure and function. Gastroenterology 135(2): 671–679CrossRefPubMedGoogle Scholar
  93. 93.
    Taura K et al (2008) Hepatic stellate cells secrete angiopoietin 1 that induces angiogenesis in liver fibrosis. Gastroenterology 135(5):1729–1738CrossRefPubMedGoogle Scholar
  94. 94.
    Yang L et al (2008) Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells. J Hepatol 48(1):98–106CrossRefPubMedGoogle Scholar
  95. 95.
    Friedman SL, Millward-Sadler H, Arthur MJP (1992) Liver fibrosis and cirrhosis. Wright’s liver and biliary disease, 3rd edn. WB Saunders, LondonGoogle Scholar
  96. 96.
    Friedman SL, Arthur MJP (2002) Reversing hepatic fibrosis. Sci Med 8(4):194–205Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.Division of Liver DiseasesMount Sinai School of MedicineNew YorkUSA

Personalised recommendations