Changing the pathogenetic roadmap of liver fibrosis? Where did it start; Where will it go?

Journal of Gastroenterology and Hepatology (Australia)

Volumn 23, Issue 7 PT1, 2008, Pages 1024-1035

  Gressner, Olav A ^a   Rizk, Mohamed S ^a   Kovalenko, Evgeniya ^a   Weiskirchen, Ralf ^a   Gressner, Axel M ^a  

^a UNIVERSITY HOSPITAL RWTH AACHEN   (Germany)

Author keywords

Diagnostic options; Epithelial mesenchymal transition; Hepatic stellate cells; Liver fibrogenesis; Liver fibrosis; Therapeutic options

Indexed keywords

ANGIOTENSIN ANTAGONIST; BIOLOGICAL MARKER; CANNABINOID RECEPTOR ANTAGONIST; CONNECTIVE TISSUE GROWTH FACTOR; CYTOKINE; ENDOTHELIN RECEPTOR ANTAGONIST; HALOFUGINONE; OSTEOGENIC PROTEIN 1; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA AGONIST; PIRFENIDONE; PROTEINASE INHIBITOR; SCAVENGER; TRANSFORMING GROWTH FACTOR BETA; TRICHOSTATIN A;

BONE MARROW CELL; CELL DIFFERENTIATION; CELL TRANSFORMATION; EPITHELIUM CELL; EXTRACELLULAR MATRIX; FIBROGENESIS; HUMAN; ITO CELL; LIVER FIBROSIS; MESENCHYME; MYOFIBROBLAST; PATHOPHYSIOLOGY; PERICYTE; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; STELLATE CELL; STEM CELL;

EID: 47649091388     PISSN: 08159319     EISSN: 14401746     Source Type: Journal    
DOI: 10.1111/j.1440-1746.2008.05345.x     Document Type: Review

References (173)

1. Hartroft WS. The trabecular anatomy of late stages of experimental dietary cirrhosis. Anat. Rec. 1954 119 : 71 94.
2. Anthony PP, Ishak KG, Nayak NC, Poulsen HE, Scheuer PJ, Sobin LH. The morphology of cirrhosis. J. Clin. Pathol. 1978 31 : 395 414.
3. McGee JO, Patrick RS. The role of perisinusoidal cells in hepatic fibrogenesis. Lab. Invest. 1972 26 : 429 40.
4. Kent G, Gay S, Inouye T, Bahu R, Minick OT, Popper H. Vitamin A-containing lipocytes and formation of type III collagen in liver injury. Proc. Natl. Acad. Sci. U.S.A. 1976 73 : 3719 22.
5. Kent G, Minick T, Inouye T. Nature and role of vitamin A-storing cells. J. Cell Biol. 1977 75 : 193a.
6. Kent G, Inouye T, Minick OT, Bahu RM. Role of lipocytes (perisinusoidal cells) in fibrogenesis. In : Wisse E, Knook DL, eds. Kupffer Cells and Other Liver Sinusoidal Cells. Amsterdam : Elsevier/North-Holland Biomedical Press, 1977 73 82.
7. Boll F. Die Bindesubstanz der Drüsen. Arch. Mikrosk. Anat. 1869 4 : 334 55.
8. Kupffer K. Über Sternzellen der Leber. Briefliche Mitteilung an Professor Waldeyer. Arch. Mikrosk. Anat. 1876 12 : 353 8.
9. Ito T, Nemoto J. Über die Kupfferschen Sternzellen und die 'Fettspeicherungszellen' ('fat-storing cells') in der Blutkapillarenwand der menschlichen Leber. Okajimas Folia Anat. Jpn. 1952 24 : 243 58.
10. Wake K. Sternzellen in the liver: perisinusoidal cells with special reference to storage of vitamin A. Am. J. Anat. 1971 132 : 429 62.
11. Aterman K. The parasinusoidal cells of the liver: a historical account. Histochem. J. 1986 18 : 279 305.
12. Zimmermann KW. Der feinere Bau der Blutcapillaren. Z. Anat. Entwicklungsgesch. 1923 68 : 29 109.
13. Bronfenmajer S, Schaffner F, Popper H. Fat storing cells (lipocytes) in human liver. Arch. Pathol. 1966 82 : 447 53.
14. Ahern M, Hall P, Halliday J et al. Hepatic stellate cell nomenclature. Hepatology 1996 23 : 193.
15. Sato M, Suzuki S, Senoo H. Hepatic stellate cells: unique characteristics in cell biology and phenotype. Cell Struct. Funct. 2003 28 : 105 12.
16. Geerts A. History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells. Semin. Liver Dis. 2001 21 : 311 35.
17. Knook DL, Seffelaar AM, De Leeuw AM. Fat storing cells of the rat liver. Their isolation and purification. Exp. Cell Res. 1982 139 : 468 71.
18. DeLeeuw AM, McCarthy SP, Geerts A, Knook DL. Purified rat liver fat-storing cells in culture divide and contain collagen. Hepatology 1984 4 : 392 403.
19. Friedman SL, Rockey DC, McGuire RF, Maher JJ, Boyles JK, Yamasaki G. Isolated hepatic lipocytes and Kupffer cells from normal human liver: morphological and functional characteristics in primary culture. Hepatology 1992 15 : 234 43.
20. Friedman SL, Roll FJ, Boyles J, Bissell DM. Hepatic lipocytes: the principal collagen-producing cells of normal rat liver. Proc. Natl. Acad. Sci. U.S.A. 1985 82 : 8681 5.
21. Schäfer S, Zerbe O, Gressner AM. The synthesis of proteoglycans in fat storing cells of rat liver. Hepatology 1987 7 : 680 7.
22. Arenson DM, Friedman SL, Bissell DM. Formation of extracellular matrix in normal rat liver: lipocytes as a major source of proteoglycan. Gastroenterology 1988 95 : 441 7.
23. Gressner AM, Haarmann R. Hyaluronic acid synthesis and secretion by rat liver fat storing cells (perisinusoidal lipocytes) in culture. Biochem. Biophys. Res. Commun. 1988 151 : 222 9.
24. Ramadori G, Rieder H, Theiss F, Meyer zum Büschenfelde KH. Fat storing (Ito) cells of rat liver synthesize and secrete apolipoproteins: comparison with hepatocytes. Gastroenterology 1989 97 : 163 72.
25. Ramadori G, Schwögler S, Veit T et al. Tenascin gene expression in rat liver and in rat liver cells. Virchows Arch. B Cell Pathol. 1991 60 : 145 53.
26. Zhao L, Burt AD. The diffuse stallate cell system. J. Mol. Hist. 2007 38 : 53 64.
27. Schuppan D, Gressner AM. Function and metabolism of collagens and other extracellular matrix proteins. In : Bircher J, Benhamou JP, McIntyre N, Rizzetto M, Rodés J, eds. Oxford Textbook of Clinical Hepatology. Oxford : Oxford Medical Publications, 1999 381 407.
28. Schuppan D, Ruehl M, Somasundaram R, Hahn EG. Matrix as a modulator of hepatic fibrogenesis. Semin. Liver Dis. 2001 21 : 351 72.
29. Gressner AM, Weiskirchen R. Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-beta as major players and therapeutic targets. J. Cell Mol. Med. 2006 10 : 76 99.
30. de Caestecker MP, Piek E, Roberts AB. Role of transforming growth factor-beta signaling in cancer. J. Natl. Cancer Inst. 2000 92 : 1388 402.
31. Bataller R, Brenner DA. Liver fibrosis. J. Clin. Invest. 2005 115 : 209 18.
32. Tsukada S, Parsons CJ, Rippe RA. Mechanisms of liver fibrosis. Clin. Chim. Acta 2006 364 : 33 60.
33. Bataller R, North KE, Brenner DA. Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal. Hepatology 2003 37 : 493 503.
34. Hillebrandt S, Wasmuth HE, Weiskirchen R et al. Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans. Nat. Genet. 2005 37 : 835 43.
35. Rockey DC. Antifibrotic therapy in chronic liver disease. Clin. Gastroenterol. Hepatol. 2005 3 : 95 107.
36. Schaffner F, Popper H. Capillarization of hepatic sinusoids in man. Gastroenterology 1963 44 : 239 42.
37. Friedman SL. Mechanisms of disease: mechanisms of hepatic fibrosis and therapeutic implications. Nat. Clin. Pract. Gastr. 2004 1 : 98 105.
38. Wake K. Hepatic stellate cells: three-dimensional structure, localization, heterogeneity and development. Proc. Jpn. Acad. 2006 82 : 155 64.
39. Marcos R, Rocha E, Henrique RMF, Monteiro RAF. A new approach to an unbiased estimate of the hepatic stellate cell index in the rat liver: an example in healthy conditions. J. Histochem. Cytochem. 2003 51 : 1101 4.
40. Blomhoff R, Wake K. Perisinusoidal stellate cells of the liver: important roles in retinol metabolism and fibrosis. FASEB J. 1991 5 : 271 7.
41. Winau F, Hegasy G, Weiskirchen R et al. Ito cells are liver-resident antigen-presenting cells for activating T cell responses. Immunity 2007 26 : 117 29.
42. Maubach G, Lim MCC, Kumar S, Zhuo L. Expression and upregulation of cathepsin S and other early molecules required for antigen presentation in activated hepatic stellate cells upon IFN-[gamma] treatment. Biochim. Biophys. Acta-Mol. Cell Res. 2007 1773 : 219 31.
43. Vinas O, Bataller R, Sancho-Bru P et al. Human hepatic stellate cells show features of antigen-presenting cells and stimulate lymphocyte proliferation. Hepatology 2003 38 : 919 29.
44. Kordes C, Sawitza I, Muller-Marbach A et al. CD133+ hepatic stellate cells are progenitor cells. Biochem. Biophys. Res. Commun. 2007 352 : 410 17.
45. Canbay A, Taimr P, Torok N, Higuchi H, Friedman S, Gores GJ. Apoptotic body engulfment by a human stellate cell line is profibrogenic. Lab. Invest. 2003 83 : 655 63.
46. Zhan S-S, Jiang JX, Wu J et al. Phagocytosis of apoptotic bodies by hepatic stellate cells induces NADPH oxidase and is associated with liver fibrosis in vivo. Hepatology 2006 43 : 435 43.
47. Benyon RC, Iredale JP, Goddard S, Winwood PJ, Arthur MJP. Expression of tissue inhibitor of metalloproteinases 1 and 2 is increased in fibrotic human liver. Gastroenterology 1996 110 : 821 31.
48. Benyon RC, Arthur MJP. Extracellular matrix degradation and the role of hepatic stellate cells. Semin. Liver Dis. 2001 21 : 373 84.
49. Passino MA, Adams RA, Sikorski SL, Akassoglou K. Regulation of hepatic stellate cell differentiation by the neurotrophin receptor p75NTR. Science 2007 315 : 1853 6.
50. Lee JS, Semela D, Iredale J, Shah VH. Sinusoidal remodeling and angiogenesis: a new function for the liver-specific pericytes? Hepatology 2007 45 : 817 25.
51. Bataller R, Gines P, Nicolas JM et al. Angiotensin II induces contraction and proliferation of human hepatic stellate cells. Gastroenterology 2000 118 : 1149 56.
52. Bataller R, Nicolas JM, Gines P et al. Arginine vasopressin induces contraction and stimulates growth of cultured human hepatic stellate cells. Gastroenterology 1997 113 : 615 24.
53. Rockey D. Hepatic blood flow regulation by stellate cells in normal and injured liver. Semin. Liver Dis. 2001 21 : 337 49.
54. Reynaert H, Thompson MG, Thomas T, Geerts A. Hepatic stellate cells: role in microcirculation and pathophysiology of portal hypertension. Gut 2002 50 : 571 81.
55. Gressner AM. Transdifferentiation of hepatic stellate cells (Ito cells) to myofibroblasts: a key event in hepatic fibrogenesis. Kidney Int. 1996 49 : S39 45.
56. Gressner AM, Lahme B, Brenzel A. Molecular dissection of the mitogenic effect of hepatocytes on cultured hepatic stellate cells. Hepatology 1995 22 : 1507 18.
57. Gressner AM, Gao C. A cascade-mechanism of fat storing cell activation forms the basis of the fibrogenic reaction of the liver. Verh. Dtsch. Ges. Pathol. 1995 79 : 1 14.
58. Gressner AM, Lotfi S, Gressner G, Lahme B. Identification and partial characterization of a hepatocyte-derived factor promoting proliferation of cultured fat storing cells (parasinusoidal lipocytes). Hepatology 1992 16 : 1250 66.
59. Gressner AM, Lahme B. Inhibitory actions of hepatocyte plasma membranes on proliferation, protein- and proteoglycan synthesis of cultured rat fat storing cells. In : Wisse E, Knook DL, McCuskey RS, eds. Cells of the Hepatic Sinusoid, Vol. 3. Leiden : The Kupffer Cell Foundation, 1991 237 41.
60. Gressner AM, Lotfi S, Gressner G, Haltner E, Kropf J. Synergism between hepatocytes and Kupffer cells in the activation of fat storing cells (perisinusoidal lipocytes). J. Hepatol. 1993 19 : 117 32.
61. Gressner AM, Lahme B. Treatment of rat hepatocytes with transforming growth factor-beta1 increases their mitogenic activity for cultured fat storing cells. Inter. Hepatol. Commun. 1995 4 : 94 101.
62. Roth S, Michel K, Gressner AM. (Latent) transforming growth factor-beta in liver parenchymal cells, its injury-dependent release and paracrine effects on hepatic stellate cells. Hepatology 1998 27 : 1003 12.
63. Hoffmann Ch, Lahme B, Brenzel A, Gressner AM. The relation between hepatocellular damage and activation of fat storing cell proliferation in vitro. Inter. Hepatol. Commun. 1994 2 : 29 36.
64. Bachem. MG, Melchior R, Gressner AM. The role of thrombocytes in liver fibrogenesis. Effects of platelet lysate and thrombocyte-derived growth factors on the mitogenic activity and glycosaminoglycan synthesis of cultured rat liver fat storing cells. J. Clin. Chem. Clin. Biochem. 1989 27 : 555 65.
65. Decker K. Biologically active products of stimulated liver macrophages (Kupffer cells). Eur. J. Biochem. 1990 192 : 245 61.
66. Friedman SL, Arthur MJP. Kupffer cell mediated proliferation of lipocytes occurs via induction of receptors for platelet-derived growth factor - studies in rats and humans. Hepatology 1989 10 : 632.
67. Gressner AM, Haarmann R. Regulation of hyaluronate synthesis in rat liver fat storing cell cultures by Kupffer cells. J. Hepatol. 1988 7 : 310 18.
68. Gressner AM, Zerbe O. Kupffer cell-mediated induction of synthesis and secretion of proteoglycans by rat liver fat storing cells in culture. J. Hepatol. 1987 5 : 299 310.
69. Nieto N. Oxidative-stress and IL-6 mediate the fibrogenic effects of rodent Kupffer cells in stellate cells. Hepatology 2006 44 : 1487 501.
70. Adachi T, Togashi H, Suzuki A et al. NAD (P) H oxidase plays a crucial role in PDGF-induced proliferation of hepatic stellate cells. Hepatology 2005 41 : 1272 81.
71. Baroni GS, D'Ambrosio L, Ferretti G et al. Fibrogenic effect of oxidative stress on rat hepatic stellate cells. Hepatology 1998 27 : 720 6.
72. Casini A, Ceni E, Salzano R et al. Neutrophil-derived superoxide anion induces lipid peroxidation and stimulates collagen synthesis in human hepatic stellate cells: role of nitric oxide. Hepatology 1997 25 : 361 7.
73. Boschung HT. The Audubon Society Field Guide to North American Fishes, Whales, and Dolphins. New York : Knopf: Distributed by Random House, 1983.
74. Casini A, Galli G, Salzano R et al. Acetaldehyde induces c-fos and c-jun proto-oncogenes in fat-storing cell cultures through protein kinase C activation. Alcohol 1994 29 : 303 14.
75. Anania FA, Womack L, Potter JJ, Mezey E. Acetaldehyde enhances murine alpha(2)(I) collagen promoter activity by Ca2+-independent protein kinase C activation in cultured rat hepatic stellate cells. Alcohol. Clin. Exp. Res. 1999 23 : 279 84.
76. Svegliati-Baroni G, Ridolfi F, di Sario A et al. Intracellular signaling pathways involved in acetaldehyde-induced collagen and fibronectin gene expression in human hepatic stellate cells. Hepatology 2001 33 : 1130 40.
77. Corpechot C, Barbu V, Wendum D et al. Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis. Hepatology 2002 35 : 1010 21.
78. Reeves HL, Friedman SL. Activation of hepatic stellate cells - A key issue in liver fibrosis. Front. Biosci. 2002 7 : D808 26.
79. Gressner AM, Weiskirchen R, Breitkopf K, Dooley S. Roles of TGF-β in hepatic fibrosis. Front. Biosci. 2002 7 : D793 807.
80. Gabele E, Brenner DA, Rippe RA. Liver fibrosis: signals leading to the amplification of the fibrogenic hepatic stellate cell. Front. Biosci. 2003 8 : D69 77.
81. Inagaki Y, Okazaki I. Emerging insights into Transforming growth factor {beta} Smad signal in hepatic fibrogenesis. Gut 2007 56 : 284 92.
82. Feige JJ, Baird A. Crinopexy: extracellular regulation of growth factor action. Kidney Int. 1995 47 (Suppl. 49 S15 18.
83. Pinzani M, Marra F. Cytokine receptors and signaling in hepatic stellate cells. Semin. Liver Dis. 2001 21 : 397 416.
84. Bissell DM, Wang SS, Jarnagin WR, Roll FJ. Cell-specific expression of transforming growth factor-beta in rat liver - Evidence for autocrine regulation of hepatocyte proliferation. J. Clin. Invest. 1995 96 : 447 55.
85. Marra F, Bonewald LF, Parksnyder S, Park IS, Woodruff KA, Abboud HE. Characterization and regulation of the latent transforming growth factor-beta complex secreted by vascular pericytes. J. Cell Physiol. 1996 166 : 537 46.
86. Gressner AM, Polzar B, Lahme B, Mannherz HG. Induction of rat liver parenchymal cell apoptosis by hepatic myofibroblasts via transforming growth factor-beta. Hepatology 1996 23 : 571 81.
87. Gressner AM, Lahme B, Mannherz HG, Polzar B. TGF-beta-mediated hepatocellular apoptosis by rat and human hepatoma cells and primary rat hepatocytes. J. Hepatol. 1997 26 : 1079 92.
88. Oberhammer F, Bursch W, Parzefall W et al. Effect of transforming growth factor beta on cell death of cultured rat hepatocytes. Cancer Res. 1991 51 : 2478 85.
89. Oberhammer FA, Pavelka M, Sharma S et al. Induction of apoptosis in cultured hepatocytes and in regressing liver by transforming growth factor-beta1. Proc. Natl Acad. Sci. U.S.A. 1992 89 : 5408 12.
90. Kiso S, Kawata S, Tamura S et al. Alteration in growth regulation of hepatocytes in primary culture obtained from cirrhotic rat: poor response to transforming growth factor-beta 1 and interferons. Hepatology 1994 20 : 1303 8.
91. Bissell DM, Roulot D, George J. Transforming growth factor β and the liver. Hepatology 2001 34 : 859 67.
92. Koli K, Saharinen J, Hyytiainen M, Penttinen C, Keski-Oja J. Latency, activation, and binding proteins of TGF-beta. Microsc. Res. Tech. 2001 52 : 354 62.
93. Arias M, Lahme B, Van de Leur E, Gressner AM, Weiskirchen R. Adenoviral delivery of an antisense RNA complementary to the 3′ coding sequence of transforming growth factor-β1 inhibits fibrogenic activities of hepatic stellate cells. Cell Growth Differ. 2002 13 : 265 73.
94. De Gouville AC, Huet S. Inhibition of ALK5 as a new approach to treat liver fibrotic diseases. Drug News Perspect. 2006 19 : 85 90.
95. Dooley S, Delvoux B, Lahme B, Mangasser-Stephan K, Gressner AM. Modulation of transforming growth factor beta response and signaling during transdifferentiation of rat hepatic stellate cells to myofibroblasts. Hepatology 2000 31 : 1094 106.
96. Hellerbrand C, Stefanovic B, Giordano F, Burchardt ER, Brenner DA. The role of TGF beta 1 in initiating hepatic stellate cell activation in vivo. J. Hepatol. 1999 30 : 77 87.
97. Friedman SL. Transcriptional regulation of stellate cell activation. J. Gastroenterol. Hepatol. 2006 31 : S79 83.
98. Iwamoto H, Sakai H, Nawata H. Inhibition of integrin signaling with Arg-Gly-Asp motifs in rat hepatic stellate cells. J. Hepatol. 1998 29 : 752 9.
99. Gutierrez-Ruiz M, Gomez-Quiroz LE. Liver fibrosis: searching for cell model answers. Liver Int. 2007 27 : 434 9.
100. Geerts A, Vrijsen R, Rauterberg J, Burt A, Schellinck P, Wisse E. In vitro differentiation of fat storing cells parallels marked increase of collagen synthesis and secretion. J. Hepatol. 1989 9 : 59 68.
101. Sun K, Wang Q, Huang XH. PPAR gamma inhibits growth of rat hepatic stellate cells and TGF beta-induced connective tissue growth factor expression. Acta Pharmacol. Sin. 2006 27 : 715 23.
102. De Minicis S, Seki E, Uchinami H et al. Gene expression profiles during hepatic stellate cell activation in culture and in vivo. Gastroenterology 2007 132 : 1937 46.
103. Wake K, Sato T. Intralobular heterogeneity of perisinusoidal stellate cells in porcine liver. Cell Tissue Res. 1993 273 : 227 37.
104. Ballardini G, Groff P, DeGiorgi LB, Schuppan D, Bianchi FB. Ito cell heterogeneity: desmin-negative Ito cells in normal rat liver. Hepatology 1994 19 : 440 6.
105. Zou ZZ, Ekataksin W, Wake K. Zonal and regional differences identified from precision mapping of vitamin A-storing lipid droplets of the hepatic stellate cells in pig liver: a novel concept of addressing the intralobular area of heterogeneity. Hepatology 1998 April 27 : 1098 108.
106. Geerts A, Lazou JM, De Bleser P, Wisse E. Tissue distribution, quantitation and proliferation kinetics of fat storing cells in carbon tetrachloride-injured rat liver. Hepatology 1991 13 : 1193 202.
107. Horn T, Junge J, Christoffersen P. Early alcoholic liver injury. Activation of lipocytes in acinar zone 3 and correlation to degree of collagen formation in Disse space. J. Hepatol. 1986 3 : 333 40.
108. Knittel T, Kobold D, Piscaglia F et al. 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. 1999 112 : 387 401.
109. Knittel T, Kobold D, Saile B et al. Rat liver myofibroblasts and hepatic stellate cells: different cell populations of the fibroblast lineage with fibrogenic potential. Gastroenterology 1999 117 : 1205 21.
110. Kobold D, Grundmann A, Piscaglia F et al. 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 13.
111. Magness ST, Bataller R, Yang L, Brenner DA. A dual reporter gene transgenic mouse demonstrates heterogeneity in hepatic fibrogenic cell populations. Hepatology 2004 40 : 1151 9.
112. Cassiman D, Roskams T. Beauty is in the eye of the beholder: emerging concepts and pitfalls in hepatic stellate cell research. J. Hepatol. 2002 37 : 527 35.
113. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev. Cancer 2006 6 : 392 401.
114. Ramadori G, Saile B. Portal tract fibrogenesis in the liver. Lab. Invest. 2003 84 : 153 9.
115. Ikegami T, Zhang Y, Matsuzaki Y. Liver fibrosis. Possible involvement of EMT. Cells Tissues Organs 2007 185 : 213 21.
116. Li J, Deane JA, Campanale NV, Bertram JF, Ricardo SD. The contribution of bone marrow-derived cells to the development of renal interstitial fibrosis. Stem Cells 2007 25 : 697 706.
117. Gao Zh, McAlister VC, Williams GM. Repopulation of liver endothelium by bone-marrow-derived cells. Lancet 2001 357 : 932 3.
118. Fujii H, Hirose T, Oe S et al. Contribution of bone marrow cells to liver regeneration after partial hepatectomy in mice. J. Hepatol. 2002 36 : 653 9.
119. Baba S, Fujii H, Hirose T et al. Commitment of bone marrow cells to hepatic stellate cells in mouse. J. Hepatol. 2004 40 : 255 60.
120. Russo FP, Alison MR, Bigger BW et al. The bone marrow functionally contributes to liver fibrosis. Gastroenterology 2006 130 : 1807 21.
121. Forbes SJ, Russo FP, Rey V et al. A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis. Gastroenterology 2004 126 : 955 63.
122. Kisseleva T, Uchinami H, Feirt N et al. Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis. J. Hepatol. 2006 45 : 429 38.
123. Quan TE, Cowper SE, Bucala R. The role of circulating fibrocytes in fibrosis. Curr. Rheumatol. Rep. 2006 8 : 145 50.
124. Bucala R, Spiegel LA, Chesney AH, Cerami A. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol. Med. 1994 1 : 71 81.
125. Abe R, Donnelly SC, Peng T, Bucala R, Metz CN. Peripheral blood fibrocytes: differentiation pathway and migration to wound sites. J. Immunol. 2001 166 : 7556 62.
126. Quan TE, Cowper S, Wu SP, Bockenstedt LK, Bucala R. Circulating fibrocytes: collagen-secreting cells of the peripheral blood. Int. J. Biochem. Cell Biol. 2004 36 : 598 606.
127. Strieter RM, Gomperts BN, Keane MP. The role of CXC chemokines in pulmonary fibrosis. J. Clin. Invest. 2007 117 : 549 56.
128. Ishii G, Sangai T, Sugiyama K et al. In vivo characterization of bone marrow-derived fibroblasts recruited into fibrotic lesions. Stem Cells 2005 23 : 699 706.
129. Higashiyama R, Inagaki Y, Hong YY et al. Bone marrow-derived cells express matrix metalloproteinases and contribute to regression of liver fibrosis in mice. Hepatology 2007 45 : 213 22.
130. Moore BB, Kolodsick JE, Thannickal VJ et al. CCR2-mediated recruitment of fibrocytes to the alveolar space after fibrotic injury. Am. J. Pathol. 2005 166 : 675 84.
131. Marra F. Hepatic stellate cells and the regulation of liver inflammation. J. Hepatol. 1999 31 : 1120 30.
132. Clouston AD, Powell EE, Walsh MJ, Richardson MM, Demetris AJ, Jonsson JR. Fibrosis correlates with a ductular reaction in hepatitis C: roles of impaired replication, progenitor cells and steatosis. Hepatology 2005 41 : 809 18.
133. Romagnani P, Lasagni L, Romagnani S. Peripheral blood as a source of stem cells for regenerative medicine. Exp. Opin. Biol. Ther. 2006 6 : 193 202.
134. Ruhnke M, Ungefroren H, Nussler A et al. Differentiation of in vitro-modified human peripheral blood monocytes into hepatocyte-like and pancreatic islet-like cells. Gastroenterology 2005 128 : 1774 86.
135. Ruhnke M, Nussler AK, Ungefroren H et al. Human monocyte-derived neohepatocytes: a promising alternative to primary human hepatocytes for autologous cell therapy. Transplantation 2005 79 : 1097 103.
136. Pinzani M, Abboud HE, Gesualdo L, Abboud SL. Regulation of macrophage colony-stimulating factor in liver fat-storing cells by peptide growth factors. Am. J. Physiol. 1992 262 : C876 81.
137. Marra F, Valente AJ, Pinzani M, Abboud HE. Cultured human liver fat storing cells produce monocyte chemotactic protein-1 - Regulation by proinflammatory cytokines. J. Clin. Invest. 1993 92 : 1674 80.
138. Sprenger H, Kaufmann A, Garn H, Lahme B, Gemsa D, Gressner AM. Induction of neutrophil attracting chemokines in transforming hepatic stellate cells. Gastroenterology 1997 113 : 277 85.
139. Marra F, Defranco R, Grappone C et al. Increased expression of monocyte chemotactic protein-1 during active hepatic fibrogenesis: correlation with monocyte infiltration. Am. J. Pathol. 1998 152 : 423 30.
140. Pilling D, Buckley CD, Salmon M, Gomer RH. Inhibition of fibrocyte differentiation by serum amyloid P. J. Immunol. 2003 171 : 5537 46.
141. Pilling D, Roife D, Wang M, Crawford JR, Travis EL, Gomer RH. Inhibition of bleomycin-induced pulmonary fibrosis by serum amyloid P. In : Wynn TA, Gallatin WM, Lupher M, Jr., Keystone Symposia on Molecular and Cellular Biology - Abstract Book. Tahoe City : Keystone Symposia, 2007 45 [Abstract].
142. Cassiman D, Barlow A, Vander Borght S, Libbrecht L, Pachnis V. Hepatic stellate cells do not derive from the neural crest. J. Hepatol. 2006 44 : 1098 104.
143. Geerts A. On the origin of stellate cells: mesodermal, endodermal or neuro-ectodermal? J. Hepatol. 2004 February 40 : 331 4.
144. Lee JM, Dedhar S, Kalluri R, Thompson EW. The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J. Cell Biol. 2006 172 : 973 81.
145. Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis. J. Clin. Invest. 2003 112 : 1776 84.
146. 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 50.
147. Karasek MA. Does transformation of microvascular endothelial cells into myofibroblasts play a key role in the etiology and pathology of fibrotic disease? Med. Hypotheses 2007 68 : 650 5.
148. Zeisberg M, Yang C, Martino M et al. Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J. Biol. Chem. 2007 282 : 23337 47.
149. Kaimori A, Potter J, Kaimori J, Wang C, Mezey E, Koteish A. TGF-beta 1 induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in-vitro. J. Biol. Chem. 2007 282 : 22089 101.
150. Robertson H, Kirby JA, Yip WW, Jones DEJ, Burt AD. Biliary epithelial-mesenchymal transition in posttransplantation recurrence of primary biliary cirrhosis. Hepatology 2007 45 : 977 81.
151. Rygiel KA, Robertson H, Burt AD, Jones DEJ, Kirby JA. Demonstration of the transition of intrahepatic biliary epithelial cells to fibroblasts during chronic inflammatory liver diseases. J. Hepatol. 2006 44 : S241.
152. Kinnman N, Francoz C, Barbu W et al. The myofibroblastic conversion of peribiliary fibrogenic cells distinct from hepatic stellate cells is stimulated by platelet-derived growth factor during liver fibrogenesis. Lab. Invest. 2003 83 : 163 73.
153. Beaussier M, Wendum D, Schiffer E et al. Prominent contribution of portal mesenchymal cells to liver fibrosis in ischemic and obstructive cholestatic injuries. Lab. Invest. 2007 87 : 292 303.
154. Yang Y, Pan X, Lei W et al. Regulation of transforming growth factor-{beta}1-induced apoptosis and epithelial-to-mesenchymal transition by protein kinase A and signal transducers and activators of transcription 3. Cancer Res. 2006 66 : 8617 24.
155. del Castillo G, Murillo MM, varez-Barrientos A et al. 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 71.
156. Vega S, Morales AV, Ocana OH, Valdes F, Fabregat I, Nieto MA. Snail blocks the cell cycle and confers resistance to cell death. Gene Dev. 2004 18 : 1131 43.
157. Zeisberg M, Hanai J, Sugimoto H et al. BMP-7 counteracts TGF-beta 1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat. Med. 2003 9 : 964 8.
158. Sugimoto H, Yang C, LeBleu VS et al. BMP-7 functions as a novel hormone to facilitate liver regeneration. FASEB J. 2007 21 : 256 64.
159. Wang S, Hirschberg R. Bone morphogenetic protein-7 signals opposing transforming growth factor {beta} in mesangial cells. J. Biol. Chem. 2004 279 : 23200 6.
160. ten Dijke P, Hill CS. New insights into TGF-beta-Smad signalling. Trends Biochem. Sci. 2004 29 : 265 73.
161. Neilson EG. Setting a trap for tissue fibrosis. Nat. Med. 2005 11 : 373 4.
162. Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. J. Clin. Invest. 2007 117 : 557 67.
163. Gressner O, Lahme B, Demirci I, Gressner AM, Weiskirchen R. Differential effects of TGF-beta on connective tissue growth factor (CTGF/CCN2) expression in hepatic stellate cells and hepatocytes. J. Hepatol. 2007 47 : 699 710.
164. Rachfal AW, Brigstock DR. Connective tissue growth factor (CTGF/CCN2) in hepatic fibrosis. Hepatol. Res. 2003 26 : 1 9.
165. Abreu JG, Ketpura NI, Reversade B, De Robertis EM. Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-beta. Nat. Cell Biol. 2002 4 : 599 604.
166. Abou-Shady M, Friess H, Zimmermann A et al. Connective tissue growth factor in human liver cirrhosis. Liver 2000 20 : 296 304.
167. Paradis V, Dargere D, Vidaud M et al. Expression of connective tissue growth factor in experimental rat and human liver fibrosis. Hepatology 1999 30 : 968 76.
168. Blom IE, Goldschmeding R, Leask A. Gene regulation of connective tissue growth factor: new targets for antifibrotic therapy. Matrix Biol. 2002 21 : 473 82.
169. Li G, Xie Q, Shi Y et al. Inhibition of connective tissue growth factor by siRNA prevents liver fibrosis in rats. J. Gene Med. 2006 8 : 889 900.
170. George J, Tsutsumi M. siRNA-mediated knockdown of connective tissue growth factor prevents N-nitrosodimethylamine-induced hepatic fibrosis in rats. Gene Ther. 2007 14 : 790 803.
171. Zeisberg M. Bone morphogenic protein-7 and the kidney: current concepts and open questions. Nephrol. Dial. Transplant. 2006 21 : 568 73.
172. Kinoshita K, Iimuro Y, Otogawa K et al. Adenovirus-mediated expression of BMP-7 suppresses the development of liver fibrosis in rats. Gut 2007 56 : 706 14.
173. Gressner AM, Yagmur E, Lahme B, Gressner O, Stanzel S. Connective tissue growth factor in serum as a new candidate test for assessment of hepatic fibrosis. Clin. Chem. 2006 52 : 1815 17.