Mechanisms of fibrogenesis in liver cirrhosis: The molecular aspects of epithelial-mesenchymal transition

World Journal of Hepatology

Volumn 6, Issue 4, 2014, Pages 207-216

  Lee, Sun Jae ^a   Kim, Kyung Hyun ^a   Park, Kwan Kyu ^a  

^a Catholic University of Daegu   (South Korea)

Author keywords

Biological markers; Epithelial mesenchymal transition; Fibrosis; Liver; Transforming growth factor beta1

Indexed keywords

EID: 84901227582     PISSN: None     EISSN: 19485182     Source Type: Journal    
DOI: 10.4254/wjh.v6.i4.207     Document Type: Review

References (101)

1. Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology 2008; 134: 1655-1669 [PMID: 18471545 DOI: 10.1053/ j.gastro.2008.03.003]
2. Marsillach J, Ferré N, Camps J, Rull A, Beltran R, Joven J. Changes in the expression of genes related to apoptosis and fibrosis pathways in CCl4-treated rats. Mol Cell Biochem 2008; 308: 101-109 [PMID: 17938867 DOI: 10.1007/ s11010-007-9617-0]
3. Dooley S, Hamzavi J, Ciuclan L, Godoy P, Ilkavets I, Ehnert S, Ueberham E, Gebhardt R, Kanzler S, Geier A, Breitkopf K, Weng H, Mertens PR. Hepatocyte-specific Smad7 expression attenuates TGF-beta-mediated fibrogenesis and protects against liver damage. Gastroenterology 2008; 135: 642-659 [PMID: 18602923 DOI: 10.1053/j.gastro.2008.04.038]
4. Nitta T, Kim JS, Mohuczy D, Behrns KE. Murine cirrhosis induces hepatocyte epithelial mesenchymal transition and alterations in survival signaling pathways. Hepatology 2008; 48: 909-919 [PMID: 18712785 DOI: 10.1002/hep.22397]
5. Giebeler A, Boekschoten MV, Klein C, Borowiak M, Birchmeier C, Gassler N, Wasmuth HE, Müller M, Trautwein C, Streetz KL. c-Met confers protection against chronic liver tissue damage and fibrosis progression after bile duct ligation in mice. Gastroenterology 2009; 137: 297-308, 308.e1-4 [PMID: 19208365 DOI: 10.1053/j.gastro.2009.01.068]
6. Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G. The myofibroblast: one function, multiple origins. Am J Pathol 2007; 170: 1807-1816 [PMID: 17525249 DOI: 10.2353/ajpath.2007.070112]
7. Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest 2003; 112: 1776-1784 [PMID: 14679171 DOI: 10.1172/JCI20530]
8. Russo FP, Alison MR, Bigger BW, Amofah E, Florou A, Amin F, Bou-Gharios G, Jeffery R, Iredale JP, Forbes SJ. The bone marrow functionally contributes to liver fibrosis. Gastroenterology 2006; 130: 1807-1821 [PMID: 16697743 DOI: 10.1053/j.gastro.2006.01.036]
9. Forbes SJ, Russo FP, Rey V, Burra P, Rugge M, Wright NA, Alison MR. A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis. Gastroenterology 2004; 126: 955-963 [PMID: 15057733]
10. Gao Z, McAlister VC, Williams GM. Repopulation of liver endothelium by bone-marrow-derived cells. Lancet 2001; 357: 932-933 [PMID: 11289353]
11. Fujii H, Hirose T, Oe S, Yasuchika K, Azuma H, Fujikawa T, Nagao M, Yamaoka Y. Contribution of bone marrow cells to liver regeneration after partial hepatectomy in mice. J Hepatol 2002; 36: 653-659 [PMID: 11983449]
12. Chang YJ, Liu JW, Lin PC, Sun LY, Peng CW, Luo GH, Chen TM, Lee RP, Lin SZ, Harn HJ, Chiou TW. Mesenchymal stem cells facilitate recovery from chemically induced liver damage and decrease liver fibrosis. Life Sci 2009; 85: 517-525 [PMID: 19686763 DOI: 10.1016/j.lfs.2009.08.003]
13. Kisseleva T, Uchinami H, Feirt N, Quintana-Bustamante O, Segovia JC, Schwabe RF, Brenner DA. Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis. J Hepatol 2006; 45: 429-438 [PMID: 16846660 DOI: 10.1016/ j.jhep.2006.04.014]
14. Roderfeld M, Rath T, Voswinckel R, Dierkes C, Dietrich H, Zahner D, Graf J, Roeb E. Bone marrow transplantation demonstrates medullar origin of CD34+ fibrocytes and ameliorates hepatic fibrosis in Abcb4-/- mice. Hepatology 2010; 51: 267-276 [PMID: 19827165 DOI: 10.1002/hep.23274]
15. Higashiyama R, Inagaki Y, Hong YY, Kushida M, Nakao S, Niioka M, Watanabe T, Okano H, Matsuzaki Y, Shiota G, Okazaki I. Bone marrow-derived cells express matrix metalloproteinases and contribute to regression of liver fibrosis in mice. Hepatology 2007; 45: 213-222 [PMID: 17187438 DOI: 10.1002/hep.21477]
16. Bird TG, Lorenzini S, Forbes SJ. Activation of stem cells in hepatic diseases. Cell Tissue Res 2008; 331: 283-300 [PMID: 18046579 DOI: 10.1007/s00441-007-0542-z]
17. Iredale JP. Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. J Clin Invest 2007; 117: 539-548 [PMID: 17332881 DOI: 10.1172/ JCI30542]
18. Wake K. Perisinusoidal stellate cells (fat-storing cells, interstitial cells, lipocytes), their related structure in and around the liver sinusoids, and vitamin A-storing cells in extrahepatic organs. Int Rev Cytol 1980; 66: 303-353 [PMID: 6993411]
19. Uyama N, Iimuro Y, Kawada N, Reynaert H, Suzumura K, Hirano T, Kuroda N, Fujimoto J. Fascin, a novel marker of human hepatic stellate cells, may regulate their proliferation, migration, and collagen gene expression through the FAK-PI3K-Akt pathway. Lab Invest 2012; 92: 57-71 [PMID: 22005766 DOI: 10.1038/labinvest.2011.150]
20. Mormone E, George J, Nieto N. Molecular pathogenesis of hepatic fibrosis and current therapeutic approaches. Chem Biol Interact 2011; 193: 225-231 [PMID: 21803030 DOI: 10.1016/j.cbi.2011.07.001]
21. Friedman SL. Seminars in medicine of the Beth Israel Hospital, Boston. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies. N Engl J Med 1993; 328: 1828-1835 [PMID: 8502273 DOI: 10.1056/NEJM199306243282508]
22. Pinzani M. Novel insights into the biology and physiology of the Ito cell. Pharmacol Ther 1995; 66: 387-412 [PMID: 7667403]
23. Gressner AM. Cytokines and cellular crosstalk involved in the activation of fat-storing cells. J Hepatol 1995; 22: 28-36 [PMID: 7665846]
24. Ramadori G, Veit T, Schwögler S, Dienes HP, Knittel T, Rieder H, Meyer zum Büschenfelde KH. Expression of the gene of the alpha-smooth muscle-actin isoform in rat liver and in rat fat-storing (ITO) cells. Virchows Arch B Cell Pathol Incl Mol Pathol 1990; 59: 349-357 [PMID: 1705733]
25. Iredale JP, Benyon RC, Arthur MJ, Ferris WF, Alcolado R, Winwood PJ, Clark N, Murphy G. Tissue inhibitor of metalloproteinase-messenger RNA expression is enhanced relative to interstitial collagenase messenger RNA in experimental liver injury and fibrosis. Hepatology 1996; 24: 176-184 [PMID: 8707259 DOI: 10.1002/hep.510240129]
26. Théret N, Musso O, L'Helgoualc'h A, Clément B. Activation of matrix metalloproteinase-2 from hepatic stellate cells requires interactions with hepatocytes. Am J Pathol 1997; 150: 51-58 [PMID: 9006321]
27. Pinzani M. Epithelial-mesenchymal transition in chronic liver disease: fibrogenesis or escape from death? J Hepatol 2011; 55: 459-465 [PMID: 21320559 DOI: 10.1016/j.jhep.2011.02.001]
28. Choi SS, Diehl AM. Epithelial-to-mesenchymal transitions in the liver. Hepatology 2009; 50: 2007-2013 [PMID: 19824076 DOI: 10.1002/hep.23196]
29. Yang L, Jung Y, Omenetti A, Witek RP, Choi S, Vandongen HM, Huang J, Alpini GD, Diehl AM. Fate-mapping evidence that hepatic stellate cells are epithelial progenitors in adult mouse livers. Stem Cells 2008; 26: 2104-2113 [PMID: 18511600 DOI: 10.1634/stemcells.2008-0115]
30. Kordes C, Sawitza I, Müller-Marbach A, Ale-Agha N, Keitel V, Klonowski-Stumpe H, Häussinger D. CD133+ hepatic stellate cells are progenitor cells. Biochem Biophys Res Commun 2007; 352: 410-417 [PMID: 17118341 DOI: 10.1016/ j.bbrc.2006.11.029]
31. Kinnman N, Housset C. Peribiliary myofibroblasts in biliary type liver fibrosis. Front Biosci 2002; 7: d496-d503 [PMID: 11815289]
32. Li Z, Dranoff JA, Chan EP, Uemura M, Sévigny J, Wells RG. Transforming growth factor-beta and substrate stiffness regulate portal fibroblast activation in culture. Hepatology 2007; 46: 1246-1256 [PMID: 17625791 DOI: 10.1002/hep.21792]
33. Tuchweber B, Desmoulière A, Bochaton-Piallat ML, Rubbia- Brandt L, Gabbiani G. Proliferation and phenotypic modulation of portal fibroblasts in the early stages of cholestatic fibrosis in the rat. Lab Invest 1996; 74: 265-278 [PMID: 8569191]
34. Desmoulière A, Darby I, Costa AM, Raccurt M, Tuchweber B, Sommer P, Gabbiani G. Extracellular matrix deposition, lysyl oxidase expression, and myofibroblastic differentiation during the initial stages of cholestatic fibrosis in the rat. Lab Invest 1997; 76: 765-778 [PMID: 9194853]
35. Firrincieli D, Boissan M, Chignard N. Epithelial-mesenchymal transition in the liver. Gastroenterol Clin Biol 2010; 34: 523-528 [PMID: 20615641 DOI: 10.1016/j.gcb.2010.04.017]
36. Carmona-Cuenca I, Herrera B, Ventura JJ, Roncero C, Fernández M, Fabregat I. EGF blocks NADPH oxidase activation by TGF-beta in fetal rat hepatocytes, impairing oxidative stress, and cell death. J Cell Physiol 2006; 207: 322-330 [PMID: 16331683 DOI: 10.1002/jcp.20568]
37. Eghbali-Fatourechi G, Sieck GC, Prakash YS, Maercklein P, Gores GJ, Fitzpatrick LA. Type I procollagen production and cell proliferation is mediated by transforming growth factorbeta in a model of hepatic fibrosis. Endocrinology 1996; 137: 1894-1903 [PMID: 8612529]
38. Valdés F, Alvarez AM, Locascio A, Vega S, Herrera B, Fernández M, Benito M, Nieto MA, Fabregat I. The epithelial mesenchymal transition confers resistance to the apoptotic effects of transforming growth factor Beta in fetal rat hepatocytes. Mol Cancer Res 2002; 1: 68-78 [PMID: 12496370]
39. Kaimori A, Potter J, Kaimori JY, Wang C, Mezey E, Koteish A. Transforming growth factor-beta1 induces an epithelial-tomesenchymal transition state in mouse hepatocytes in vitro. J Biol Chem 2007; 282: 22089-22101 [PMID: 17513865 DOI: 10.1074/jbc.M700998200]
40. Del Castillo G, Murillo MM, Alvarez-Barrientos A, Bertran E, Fernández M, Sánchez A, Fabregat I. Autocrine production of TGF-beta confers resistance to apoptosis after an epithelial- mesenchymal transition process in hepatocytes: Role of EGF receptor ligands. Exp Cell Res 2006; 312: 2860-2871 [PMID: 16828470 DOI: 10.1016/j.yexcr.2006.05.017]
41. Kitao A, Sato Y, Sawada-Kitamura S, Harada K, Sasaki M, Morikawa H, Shiomi S, Honda M, Matsui O, Nakanuma Y. Endothelial to mesenchymal transition via transforming growth factor-beta1/Smad activation is associated with portal venous stenosis in idiopathic portal hypertension. Am J Pathol 2009; 175: 616-626 [PMID: 19608867 DOI: 10.2353/ajpath. 2009.081061]
42. Inagaki Y, Okazaki I. Emerging insights into Transforming growth factor beta Smad signal in hepatic fibrogenesis. Gut 2007; 56: 284-292 [PMID: 17303605 DOI: 10.1136/ gut.2005.088690]
43. Rubtsov YP, Rudensky AY. TGFbeta signalling in control of T-cell-mediated self-reactivity. Nat Rev Immunol 2007; 7: 443-453 [PMID: 17525753 DOI: 10.1038/nri2095]
44. Gressner AM, Weiskirchen R, Breitkopf K, Dooley S. Roles of TGF-beta in hepatic fibrosis. Front Biosci 2002; 7: d793-d807 [PMID: 11897555]
45. Annoni G, Weiner FR, Zern MA. Increased transforming growth factor-beta 1 gene expression in human liver disease. J Hepatol 1992; 14: 259-264 [PMID: 1380023]
46. Leask A, Abraham DJ. TGF-beta signaling and the fibrotic response. FASEB J 2004; 18: 816-827 [PMID: 15117886 DOI: 10.1096/fj.03-1273rev]
47. Zavadil J, Böttinger EP. TGF-beta and epithelial-to-mesenchymal transitions. Oncogene 2005; 24: 5764-5774 [PMID: 16123809 DOI: 10.1038/sj.onc.1208927]
48. Medici D, Hay ED, Goodenough DA. Cooperation between snail and LEF-1 transcription factors is essential for TGFbeta1- induced epithelial-mesenchymal transition. Mol Biol Cell 2006; 17: 1871-1879 [PMID: 16467384 DOI: 10.1091/mbc. E05-08-0767]
49. Zavadil J, Cermak L, Soto-Nieves N, Böttinger EP. Integration of TGF-beta/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition. EMBO J 2004; 23: 1155-1165 [PMID: 14976548 DOI: 10.1038/sj.emboj.7600069]
50. Zeisberg M, Yang C, Martino M, Duncan MB, Rieder F, Tanjore H, Kalluri R. Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J Biol Chem 2007; 282: 23337-23347 [PMID: 17562716 DOI: 10.1074/jbc. M700194200]
51. Thompson EW, Newgreen DF, Tarin D. Carcinoma invasion and metastasis: a role for epithelial-mesenchymal transition? Cancer Res 2005; 65: 5991-595; discussion 5995 [PMID: 16024595 DOI: 10.1158/0008-5472.CAN-05-0616]
52. Tarin D, Thompson EW, Newgreen DF. The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res 2005; 65: 5996-6000; discussion 6000-1 [PMID: 16024596 DOI: 10.1158/0008-5472.CAN-05-0699]
53. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest 2009; 119: 1420-1428 [PMID: 19487818 DOI: 10.1172/JCI39104]
54. Liu Y. Epithelial to mesenchymal transition in renal fibrogenesis: pathologic significance, molecular mechanism, and therapeutic intervention. J Am Soc Nephrol 2004; 15: 1-12 [PMID: 14694152]
55. Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transitions. J Clin Invest 2009; 119: 1429-1437 [PMID: 19487819 DOI: 10.1172/JCI36183]
56. Acloque H, Adams MS, Fishwick K, Bronner-Fraser M, Nieto MA. Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease. J Clin Invest 2009; 119: 1438-1449 [PMID: 19487820 DOI: 10.1172/JCI38019]
57. Okada H, Danoff TM, Kalluri R, Neilson EG. Early role of Fsp1 in epithelial-mesenchymal transformation. Am J Physiol 1997; 273: F563-F574 [PMID: 9362334]
58. Strutz F, Okada H, Lo CW, Danoff T, Carone RL, Tomasze-wski JE, Neilson EG. Identification and characterization of a fibroblast marker: FSP1. J Cell Biol 1995; 130: 393-405 [PMID: 7615639]
59. Yang J, Liu Y. Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis. Am J Pathol 2001; 159: 1465-1475 [PMID: 11583974 DOI: 10.1016/S0002-9440(10)62533-3]
60. Iwano M, Plieth D, Danoff TM, Xue C, Okada H, Neilson EG. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest 2002; 110: 341-350 [PMID: 12163453 DOI: 10.1172/JCI15518]
61. Sicklick JK, Choi SS, Bustamante M, McCall SJ, Pérez EH, Huang J, Li YX, Rojkind M, Diehl AM. Evidence for epithelial-mesenchymal transitions in adult liver cells. Am J Physiol Gastrointest Liver Physiol 2006; 291: G575-G583 [PMID: 16710052 DOI: 10.1152/ajpgi.00102.2006]
62. Masszi A, Speight P, Charbonney E, Lodyga M, Nakano H, Szászi K, Kapus A. Fate-determining mechanisms in epithelial-myofibroblast transition: major inhibitory role for Smad3. J Cell Biol 2010; 188: 383-399 [PMID: 20123992 DOI: 10.1083/jcb.200906155]
63. Fan L, Sebe A, Péterfi Z, Masszi A, Thirone AC, Rotstein OD, Nakano H, McCulloch CA, Szászi K, Mucsi I, Kapus A. Cell contact-dependent regulation of epithelial-myofibroblast transition via the rho-rho kinase-phospho-myosin pathway. Mol Biol Cell 2007; 18: 1083-1097 [PMID: 17215519 DOI: 10.1091/mbc.E06-07-0602]
64. Masszi A, Fan L, Rosivall L, McCulloch CA, Rotstein OD, Mucsi I, Kapus A. Integrity of cell-cell contacts is a critical regulator of TGF-beta 1-induced epithelial-to-myofibroblast transition: role for beta-catenin. Am J Pathol 2004; 165: 1955-1967 [PMID: 15579439]
65. Hay ED, Zuk A. Transformations between epithelium and mesenchyme: normal, pathological, and experimentally induced. Am J Kidney Dis 1995; 26: 678-690 [PMID: 7573028]
66. Xu J, Lamouille S, Derynck R. TGF-beta-induced epithelial to mesenchymal transition. Cell Res 2009; 19: 156-172 [PMID: 19153598 DOI: 10.1038/cr.2009.5]
67. Chu AS, Diaz R, Hui JJ, Yanger K, Zong Y, Alpini G, Stanger BZ, Wells RG. Lineage tracing demonstrates no evidence of cholangiocyte epithelial-to-mesenchymal transition in murine models of hepatic fibrosis. Hepatology 2011; 53: 1685-1695 [PMID: 21520179 DOI: 10.1002/hep.24206]
68. Lin SL, Kisseleva T, Brenner DA, Duffield JS. Pericytes and perivascular fibroblasts are the primary source of collagenproducing cells in obstructive fibrosis of the kidney. Am J Pathol 2008; 173: 1617-1627 [PMID: 19008372 DOI: 10.2353/ ajpath.2008.080433]
69. Yamaoka K, Nouchi T, Marumo F, Sato C. Alpha-smoothmuscle actin expression in normal and fibrotic human livers. Dig Dis Sci 1993; 38: 1473-1479 [PMID: 8344103]
70. Wells RG. The epithelial-to-mesenchymal transition in liver fibrosis: here today, gone tomorrow? Hepatology 2010; 51: 737-740 [PMID: 20198628 DOI: 10.1002/hep.23529]
71. Le Hir M, Hegyi I, Cueni-Loffing D, Loffing J, Kaissling B. Characterization of renal interstitial fibroblast-specific protein 1/S100A4-positive cells in healthy and inflamed rodent kidneys. Histochem Cell Biol 2005; 123: 335-346 [PMID: 15856273 DOI: 10.1007/s00418-005-0788-z]
72. Mendez MG, Kojima S, Goldman RD. Vimentin induces changes in cell shape, motility, and adhesion during the epithelial to mesenchymal transition. FASEB J 2010; 24: 1838-1851 [PMID: 20097873 DOI: 10.1096/fj.09-151639]
73. Taura K, Miura K, Iwaisako K, Osterreicher CH, Kodama Y, Penz-Osterreicher M, Brenner DA. Hepatocytes do not undergo epithelial-mesenchymal transition in liver fibrosis in mice. Hepatology 2010; 51: 1027-1036 [PMID: 20052656 DOI: 10.1002/hep.23368]
74. Milani S, Herbst H, Schuppan D, Stein H, Surrenti C. Transforming growth factors beta 1 and beta 2 are differentially expressed in fibrotic liver disease. Am J Pathol 1991; 139: 1221-1229 [PMID: 1750499]
75. Pinzani M, Milani S, Herbst H, DeFranco R, Grappone C, Gentilini A, Caligiuri A, Pellegrini G, Ngo DV, Romanelli RG, Gentilini P. Expression of platelet-derived growth factor and its receptors in normal human liver and during active hepatic fibrogenesis. Am J Pathol 1996; 148: 785-800 [PMID: 8774134]
76. Grappone C, Pinzani M, Parola M, Pellegrini G, Caligiuri A, DeFranco R, Marra F, Herbst H, Alpini G, Milani S. Expression of platelet-derived growth factor in newly formed cholangiocytes during experimental biliary fibrosis in rats. J Hepatol 1999; 31: 100-109 [PMID: 10424289]
77. Kinnman N, Hultcrantz R, Barbu V, Rey C, Wendum D, Poupon R, Housset C. PDGF-mediated chemoattraction of hepatic stellate cells by bile duct segments in cholestatic liver injury. Lab Invest 2000; 80: 697-707 [PMID: 10830780]
78. Pinzani M, Milani S, De Franco R, Grappone C, Caligiuri A, Gentilini A, Tosti-Guerra C, Maggi M, Failli P, Ruocco C, Gentilini P. Endothelin 1 is overexpressed in human cirrhotic liver and exerts multiple effects on activated hepatic stellate cells. Gastroenterology 1996; 110: 534-548 [PMID: 8566602]
79. Caligiuri A, Glaser S, Rodgers RE, Phinizy JL, Robertson W, Papa E, Pinzani M, Alpini G. Endothelin-1 inhibits secretin-stimulated ductal secretion by interacting with ETA receptors on large cholangiocytes. Am J Physiol 1998; 275: G835-G846 [PMID: 9756516]
80. Marra F, DeFranco R, Grappone C, Milani S, Pastacaldi S, Pinzani M, Romanelli RG, Laffi G, Gentilini P. Increased expression of monocyte chemotactic protein-1 during active hepatic fibrogenesis: correlation with monocyte infiltration. Am J Pathol 1998; 152: 423-430 [PMID: 9466568]
81. Omenetti A, Porrello A, Jung Y, Yang L, Popov Y, Choi SS, Witek RP, Alpini G, Venter J, Vandongen HM, Syn WK, Baroni GS, Benedetti A, Schuppan D, Diehl AM. Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans. J Clin Invest 2008; 118: 3331-3342 [PMID: 18802480 DOI: 10.1172/JCI35875]
82. Rygiel KA, Robertson H, Marshall HL, Pekalski M, Zhao L, Booth TA, Jones DE, Burt AD, Kirby JA. Epithelial-mesenchymal transition contributes to portal tract fibrogenesis during human chronic liver disease. Lab Invest 2008; 88: 112-123 [PMID: 18059363 DOI: 10.1038/labinvest.3700704]
83. Hartley JL, Davenport M, Kelly DA. Biliary atresia. Lancet 2009; 374: 1704-1713 [PMID: 19914515 DOI: 10.1016/ S0140-6736(09)60946-6]
84. Díaz R, Kim JW, Hui JJ, Li Z, Swain GP, Fong KS, Csiszar K, Russo PA, Rand EB, Furth EE, Wells RG. Evidence for the epithelial to mesenchymal transition in biliary atresia fibrosis. Hum Pathol 2008; 39: 102-115 [PMID: 17900655 DOI: 10.1016/j.humpath.2007.05.021]
85. Xia JL, Dai C, Michalopoulos GK, Liu Y. Hepatocyte growth factor attenuates liver fibrosis induced by bile duct ligation. Am J Pathol 2006; 168: 1500-1512 [PMID: 16651617 DOI: 10.2353/ajpath.2006.050747]
86. Scholten D, Osterreicher CH, Scholten A, Iwaisako K, Gu G, Brenner DA, Kisseleva T. Genetic labeling does not detect epithelial-to-mesenchymal transition of cholangiocytes in liver fibrosis in mice. Gastroenterology 2010; 139: 987-998 [PMID: 20546735 DOI: 10.1053/j.gastro.2010.05.005]
87. Ng YY, Fan JM, Mu W, Nikolic-Paterson DJ, Yang WC, Huang TP, Atkins RC, Lan HY. Glomerular epithelialmyofibroblast transdifferentiation in the evolution of glomerular crescent formation. Nephrol Dial Transplant 1999; 14: 2860-2872 [PMID: 10570089]
88. Fan JM, Ng YY, Hill PA, Nikolic-Paterson DJ, Mu W, Atkins RC, Lan HY. Transforming growth factor-beta regulates tubular epithelial-myofibroblast transdifferentiation in vitro. Kidney Int 1999; 56: 1455-1467 [PMID: 10504497 DOI: 10.1046/j.1523-1755.1999.00656.x]
89. Gershengorn MC, Hardikar AA, Wei C, Geras-Raaka E, Marcus-Samuels B, Raaka BM. Epithelial-to-mesenchymal transition generates proliferative human islet precursor cells. Science 2004; 306: 2261-2264 [PMID: 15564314 DOI: 10.1126/ science.1101968]
90. Russ HA, Ravassard P, Kerr-Conte J, Pattou F, Efrat S. Epithelial-mesenchymal transition in cells expanded in vitro from lineage-traced adult human pancreatic beta cells. PLoS One 2009; 4: e6417 [PMID: 19641613 DOI: 10.1371/journal. pone.0006417]
91. Godoy P, Hengstler JG, Ilkavets I, Meyer C, Bachmann A, Müller A, Tuschl G, Mueller SO, Dooley S. Extracellular matrix modulates sensitivity of hepatocytes to fibroblastoid dedifferentiation and transforming growth factor beta-induced apoptosis. Hepatology 2009; 49: 2031-2043 [PMID: 19274752 DOI: 10.1002/hep.22880]
92. Guarino M, Rubino B, Ballabio G. The role of epithelial-mesenchymal transition in cancer pathology. Pathology 2007; 39: 305-318 [PMID: 17558857 DOI: 10.1080/00313020701329914]
93. Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, Hung MC. Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol 2004; 6: 931-940 [PMID: 15448698 DOI: 10.1038/ncb1173]
94. Ramadori G, Saile B. Portal tract fibrogenesis in the liver. Lab Invest 2004; 84: 153-159 [PMID: 14688800 DOI: 10.1038/labinvest. 3700030]
95. Dubuisson L, Lepreux S, Bioulac-Sage P, Balabaud C, Costa AM, Rosenbaum J, Desmoulière A. Expression and cellular localization of fibrillin-1 in normal and pathological human liver. J Hepatol 2001; 34: 514-522 [PMID: 11394650]
96. Saile B, Matthes N, Neubauer K, Eisenbach C, El-Armouche H, Dudas J, Ramadori G. Rat liver myofibroblasts and hepatic stellate cells differ in CD95-mediated apoptosis and response to TNF-alpha. Am J Physiol Gastrointest Liver Physiol 2002; 283: G435-G444 [PMID: 12121892 DOI: 10.1152/ajpgi. 00441.2001]
97. Knittel T, Kobold D, Saile B, Grundmann A, Neubauer K, Piscaglia F, Ramadori G. Rat liver myofibroblasts and hepatic stellate cells: different cell populations of the fibroblast lineage with fibrogenic potential. Gastroenterology 1999; 117: 1205-1221 [PMID: 10535885]
98. Kobold D, Grundmann A, Piscaglia F, Eisenbach C, Neubauer K, Steffgen J, Ramadori G, Knittel T. Expression of reelin in hepatic stellate cells and during hepatic tissue repair: a novel marker for the differentiation of HSC from other liver myofibroblasts. J Hepatol 2002; 36: 607-613 [PMID: 11983443]
99. Cassiman D, Libbrecht L, Desmet V, Denef C, Roskams T. Hepatic stellate cell/myofibroblast subpopulations in fibrotic human and rat livers. J Hepatol 2002; 36: 200-209 [PMID: 11830331]
100. Dranoff JA, Kruglov EA, Robson SC, Braun N, Zimmermann H, Sévigny J. The ecto-nucleoside triphosphate diphosphohydrolase NTPDase2/CD39L1 is expressed in a novel functional compartment within the liver. Hepatology 2002; 36: 1135-1144 [PMID: 12395323 DOI: 10.1053/jhep.2002.36823]
101. Nakatani K, Seki S, Kawada N, Kobayashi K, Kaneda K. Expression of neural cell adhesion molecule (N-CAM) in perisinusoidal stellate cells of the human liver. Cell Tissue Res 1996; 283: 159-165 [PMID: 8581955]