Journal Mobile Options
Table of Contents
Vol. 185, No. 1-3, 2007
Issue release date: June 2007
Cells Tissues Organs 2007;185:213–221

Liver Fibrosis: Possible Involvement of EMT

Ikegami T. · Zhang Y. · Matsuzaki Y.
aDivision of Gastroenterology and Hepatology, Tokyo Medical University, Kasumigaura Hospital, Inashiki-gun, and bGraduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba City, Japan

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


Hepatic fibrosis is a wound-healing process in the liver with acute and chronic injury and is characterized by an excess production and deposition of extracellular matrix components. Hepatic stellate cells as well as portal fibroblasts play a pivotal role in the liver fibrogenesis. Regarding the origin of these mesenchymal cells, two hypotheses emerge. One hypothesis argues in favor of BM-derived progenitor cells and a second hypothesis favors epithelial-mesenchymal transition (EMT) in the local formation of these mesenchymal cells from hepatic epithelium. In this short review, we describe (1) the principle mechanisms of hepatic fibrosis, (2) the cells which play a crucial role in hepatic fibrosis, and (3) the possible involvement of EMT in the process of hepatic fibrosis and carcinogenesis.

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  1. Arthur, M.J. (2002) Reversibility of liver fibrosis and cirrhosis following treatment for hepatitis C. Gastroenterology 122: 1525–1528.
  2. Bataller, R., D.A. Brenner (2001) Hepatic stellate cells as a target for the treatment of liver fibrosis. Semin Liver Dis 21: 437–451.
  3. Cano, A., M.A. Perez-Moreno, I. Rodrigo, A. Locascio, M.J. Blanco, M.G. del Barrio, F. Portillo, M.A. Nieto (2000) The transcription factor Snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2: 76–83.
  4. Cassiman, D., L. Libbrecht, V. Desmet, C. Denef, T. Roskams (2002) Hepatic stellate cell/myofibroblast subpopulations in fibrotic human and rat livers. J Hepatol 36: 200–209.
  5. Cassiman, D., J. van Pelt, R. De Vos, F. Van Lommel, V. Desmet, S.H. Yap, T. Roskams (1999) Synaptophysin: a novel marker for human and rat hepatic stellate cells. Am J Pathol 155: 1831–1839.
  6. Czaja, A.J., H.A. Carpenter (2004) Decreased fibrosis during corticosteroid therapy of autoimmune hepatitis. J Hepatol 40: 646–652.
  7. Dedhar, S., B. Williams, G. Hannigan (1999) Integrin-linked kinase (ILK): a regulator of integrin and growth-factor signalling. Trends Cell Biol 9: 319–323.
  8. Desmouliere, A., C. Guyot, G. Gabbiani (2004) The stroma reaction myofibroblast: a key player in the control of tumor cell behavior. Int J Dev Biol 48(5–6): 509–517.
  9. Dixon, J.B., P.S. Bhathal, N.R. Hughes, P.E. O’Brien (2004) Nonalcoholic fatty liver disease: improvement in liver histological analysis with weight loss. Hepatology 39: 1647–1654.
  10. Dufour, J.F., R. DeLellis, M.M. Kaplan (1997) Reversibility of hepatic fibrosis in autoimmune hepatitis. Ann Intern Med 127: 981–985.
  11. Fattovich, G., T. Stroffolini, I. Zagni, F. Donato (2004) Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 127(5 suppl 1): S35–50.
  12. Flanders, K.C. (2004) Smad3 as a mediator of the fibrotic response. Int J Exp Pathol 85: 47–64.
  13. Forbes, S.J., F.P. Russo, V. Rey, P. Burra, M. Rugge, N.A. Wright, M.R. Alison (2004) A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis. Gastroenterology 126: 955–963.
  14. Friedman, S.L. (2000) Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem 275: 2247–2250.
  15. Giannelli, G., C. Bergamini, E. Fransvea, C. Sgarra, S. Antonaci (2005) Laminin-5 with transforming growth factor-beta1 induces epithelial to mesenchymal transition in hepatocellular carcinoma. Gastroenterology 129: 1375–1383.
  16. Hammel, P., A. Couvelard, D. O’Toole, A. Ratouis, A. Sauvanet, J.F. Flejou, C. Degott, J. Belghiti, P. Bernades, D. Valla, P. Ruszniewski, P. Levy (2001) Regression of liver fibrosis after biliary drainage in patients with chronic pancreatitis and stenosis of the common bile duct. N Engl J Med 344: 418–423.
  17. Hashimoto, N., H. Jin, T. Liu, S.W. Chensue, S.H. Phan (2004) Bone marrow-derived progenitor cells in pulmonary fibrosis. J Clin Invest 113: 243–252.
  18. Heathcote, E.J. (2004) Prevention of hepatitis C virus-related hepatocellular carcinoma. Gastroenterology 127(5 suppl 1): S294–302.
  19. Inagaki, Y., M. Mamura, Y. Kanamaru, P. Greenwel, T. Nemoto, K. Takehara, P. ten Dijke, A. Nakao (2001) Constitutive phosphorylation and nuclear localization of Smad3 are correlated with increased collagen gene transcription in activated hepatic stellate cells. J Cell Physiol 187: 117–123.
  20. Iredale, J.P. (2003) Cirrhosis: new research provides a basis for rational and targeted treatments. BMJ 327(7407): 143–147.
  21. Iredale, J.P., R.C. Benyon, J. Pickering, M. McCullen, M. Northrop, S. Pawley, C. Hovell, M.J. Arthur (1998) Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest 102: 538–549.
  22. Iwano, M., D. Plieth, T.M. Danoff, C. Xue, H. Okada, E.G. Neilson (2002) Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest 110: 341–350.
  23. Ju, W., A. Ogawa, J. Heyer, D. Nierhof, L. Yu, R. Kucherlapati, D.A. Shafritz, E.P. Bottinger (2006) Deletion of Smad2 in mouse liver reveals novel functions in hepatocyte growth and differentiation. Mol Cell Biol 26: 654–667.
  24. Kalluri, R., E.G. Neilson (2003) Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest 112: 1776–1784.
  25. Kinnman, N., C. Housset (2002) Peribiliary myofibroblasts in biliary type liver fibrosis. Front Biosci 7: d496–503.
  26. Knittel, T., S. Aurisch, K. Neubauer, S. Eichhorst, G. Ramadori (1996) Cell-type-specific expression of neural cell adhesion molecule (N-CAM) in Ito cells of rat liver. Up-regulation during in vitro activation and in hepatic tissue repair. Am J Pathol 149: 449–462.
  27. Knittel, T., D. Kobold, F. Piscaglia, B. Saile, K. Neubauer, M. Mehde, R. Timpl, G. Ramadori (1999a) Localization of liver myofibroblasts and hepatic stellate cells in normal and diseased rat livers: distinct roles of (myo-)fibroblast subpopulations in hepatic tissue repair. Histochem Cell Biol 112: 387–401.
  28. Knittel, T., D. Kobold, B. Saile, A. Grundmann, K. Neubauer, F. Piscaglia, G. Ramadori (1999b) Rat liver myofibroblasts and hepatic stellate cells: different cell populations of the fibroblast lineage with fibrogenic potential. Gastroenterology 117: 1205–1221.
  29. Li, Y., J. Yang, C. Dai, C. Wu, Y. Liu (2003) Role for integrin-linked kinase in mediating tubular epithelial to mesenchymal transition and renal interstitial fibrogenesis. J Clin Invest 112: 503–516.
  30. Lieubeau, B., M.F. Heymann, F. Henry, I. Barbieux, K. Meflah, M. Gregoire (1999) Immunomodulatory effects of tumor-associated fibroblasts in colorectal-tumor development. Int J Cancer 81: 629–636.
  31. Lim, Y.S., K.A. Kim, J.O. Jung, J.H. Yoon, K.S. Suh, C.Y. Kim, H.S. Lee (2002) Modulation of cytokeratin expression during in vitro cultivation of human hepatic stellate cells: evidence of transdifferentiation from epithelial to mesenchymal phenotype. Histochem Cell Biol 118: 127–136.
  32. Lim, Y.S., H.C. Lee, H.S. Lee (2006) Switch of cadherin expression from E- to N-type during the activation of rat hepatic stellate cells. Histochem Cell Biol, in press.
  33. Lin, C.Y., C.J. Lin, K.H. Chen, J.C. Wu, S.H. Huang, S.M. Wang (2006) Macrophage activation increases the invasive properties of hepatoma cells by destabilization of the adherens junction. FEBS Lett 580: 3042–3050.
  34. Liu, Y. (2004) Epithelial to mesenchymal transition in renal fibrogenesis: pathologic significance, molecular mechanism, and therapeutic intervention. J Am Soc Nephrol 15: 1–12.
  35. Magness, S.T., R. Bataller, L. Yang, D.A. Brenner (2004) A dual reporter gene transgenic mouse demonstrates heterogeneity in hepatic fibrogenic cell populations. Hepatology 40: 1151–1159.
  36. Malekzadeh, R., M. Mohamadnejad, N. Rakhshani, S. Nasseri-Moghaddam, S. Merat, S.M. Tavangar, A.A. Sohrabpour (2004) Reversibility of cirrhosis in chronic hepatitis B. Clin Gastroenterol Hepatol 2: 344–347.
  37. Masson, S., D.J. Harrison, J.N. Plevris, P.N. Newsome (2004) Potential of hematopoietic stem cell therapy in hepatology: a critical review. Stem Cells 22: 897–907.
  38. Nakano, M., C.S. Lieber (1982) Ultrastructure of initial stages of perivenular fibrosis in alcohol-fed baboons. Am J Pathol 106: 145–155.
  39. Nakano, M., T.M. Worner, C.S. Lieber (1982) Perivenular fibrosis in alcoholic liver injury: ultrastructure and histologic progression. Gastroenterology 83: 777–785.
  40. Neaud, V., S. Faouzi, J. Guirouilh, B. Le Bail, C. Balabaud, P. Bioulac-Sage, J. Rosenbaum (1997) Human hepatic myofibroblasts increase invasiveness of hepatocellular carcinoma cells: evidence for a role of hepatocyte growth factor. Hepatology 26: 1458–1466.
  41. Neubauer, K., T. Knittel, S. Aurisch, P. Fellmer, G. Ramadori (1996) Glial fibrillary acidic protein – a cell type specific marker for Ito cells in vivo and in vitro. J Hepatol 24: 719–730.
  42. Niki, T., M. Pekny, K. Hellemans, P.D. Bleser, K.V. Berg, F. Vaeyens, E. Quartier, F. Schuit, A. Geerts (1999) Class VI intermediate filament protein nestin is induced during activation of rat hepatic stellate cells. Hepatology 29: 520–527.
  43. Olaso, E., C. Salado, E. Egilegor, V. Gutierrez, A. Santisteban, P. Sancho-Bru, S.L. Friedman, F. Vidal-Vanaclocha (2003) Proangiogenic role of tumor-activated hepatic stellate cells in experimental melanoma metastasis. Hepatology 37: 674–685.
  44. Omata, M., H. Yoshida, Y. Shiratori (2005) Prevention of hepatocellular carcinoma and its recurrence in chronic hepatitis C patients by interferon therapy. Clin Gastroenterol Hepatol 3(10 suppl 2): S141–143.
  45. Pagan, R., M. Llobera, S. Vilaro (1995) Epithelial-mesenchymal transition in cultured neonatal hepatocytes. Hepatology 21: 820–831.
  46. Pagan, R., I. Martin, M. Llobera, S. Vilaro (1997) Epithelial-mesenchymal transition of cultured rat neonatal hepatocytes is differentially regulated in response to epidermal growth factor and dimethyl sulfoxide. Hepatology 25: 598–606.
  47. Paku, S., J. Schnur, P. Nagy, S.S. Thorgeirsson (2001) Origin and structural evolution of the early proliferating oval cells in rat liver. Am J Pathol 158: 1313–1323.
  48. Pares, A., J. Caballeria, M. Bruguera, M. Torres, J. Rodes (1986) Histological course of alcoholic hepatitis. Influence of abstinence, sex and extent of hepatic damage. J Hepatol 2: 33–42.
  49. Plante, I., D.G. Cyr, M. Charbonneau (2005) Involvement of the integrin-linked kinase pathway in hexachlorobenzene-induced gender-specific rat hepatocarcinogenesis. Toxicol Sci 88: 346–357.
  50. Poynard, T., J. McHutchison, M. Manns, C. Trepo, K. Lindsay, Z. Goodman, M.H. Ling, J. Albrecht (2002) Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology 122: 1303–1313.
  51. Reeves, H.L., S.L. Friedman (2002) Activation of hepatic stellate cells – a key issue in liver fibrosis. Front Biosci 7: d808–826.
  52. Russo, F.P., M.R. Alison, B.W. Bigger, E. Amofah, A. Florou, F. Amin, G. Bou-Gharios, R. Jeffery, J.P. Iredale, S.J. Forbes (2006) The bone marrow functionally contributes to liver fibrosis. Gastroenterology 130: 1807–1821.
  53. Saika, S., S. Kono-Saika, Y. Ohnishi, M. Sato, Y. Muragaki, A. Ooshima, K.C. Flanders, J. Yoo, M. Anzano, C.Y. Liu, W.W. Kao, A.B. Roberts (2004) Smad3 signaling is required for epithelial-mesenchymal transition of lens epithelium after injury. Am J Pathol 164: 651–663.
  54. Schnabl, B., Y.O. Kweon, J.P. Frederick, X.F. Wang, R.A. Rippe, D.A. Brenner (2001) The role of Smad3 in mediating mouse hepatic stellate cell activation. Hepatology 34: 89–100.
  55. Shafiei, M.S., D.C. Rockey (2006) The role of integrin-linked kinase in liver wound healing. J Biol Chem 281: 24863–24872.
  56. Sicklick, J.K., S.S. Choi, M. Bustamante, S.J. McCall, E.H. Perez, J. Huang, Y.X. Li, M. Rojkind, A.M. Diehl (2006) Evidence for epithelial-mesenchymal transitions in adult liver cells. Am J Physiol Gastrointest Liver Physiol 291: G575–G583.
  57. Spagnoli, F.M., C. Cicchini, M. Tripodi, M.C. Weiss (2000) Inhibition of MMH (Met murine hepatocyte) cell differentiation by TGF(beta) is abrogated by pre-treatment with the heritable differentiation effector FGF1. J Cell Sci 113: 3639–3647.
  58. Tsujimoto, T., S. Kuriyama, M. Yamazaki, Y. Nakatani, H. Okuda, H. Yoshiji, H. Fukui (2001) Augmented hepatocellular carcinoma progression and depressed Kupffer cell activity in rat cirrhotic livers. Int J Oncol 18: 41–47.
  59. Zhang, Y., T. Ikegami, A. Honda, T. Miyazaki, B. Bouscarel, M. Rojkind, I. Hyodo, Y. Matsuzaki (2006) Involvement of integrin-linked kinase in carbon tetrachloride-induced hepatic fibrosis in rats. Hepatology 44: 612–622.

Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50