Hepatic myofibroblasts and fibrogenic progression of chronic liver diseases

Histology and Histopathology

Volumn 30, Issue 9, 2015, Pages 1011-1032

  Novo, Erica ^a,b   Cannito, Stefania ^a,b   Morello, Elisabetta ^a,b   Paternostro, Claudia ^a,b   Bocca, Claudia ^a,b   Miglietta, Antonella ^a,b   Parola, Maurizio ^a,b  

^a UNIVERSITY OF TURIN   (Italy)

^b UNIVERSITY OF TURIN   (Italy)

Author keywords

Chronic liver diseases; Hepatic myofibroblasts; Hepatic stellate cells; Liver angiogenesis; Liver fibrogenesis; Portal myofibroblasts

Indexed keywords

DISEASE COURSE; HUMAN; LIVER CIRRHOSIS; METABOLISM; MYOFIBROBLAST; PATHOLOGY;

DISEASE PROGRESSION; HUMANS; LIVER CIRRHOSIS; MYOFIBROBLASTS;

EID: 84938632158     PISSN: 02133911     EISSN: 16995848     Source Type: Journal    
DOI: 10.4670/HH-11-623     Document Type: Review

References (144)

1. Asahina K. (2012). Hepatic stellate cell progenitor cells. J. Gastroenterol. Hepatol. 27 (Suppl 2), 80-84.
2. Asahina K., Tsai S.Y., Li P., Ishii M., Maxson R.E. Jr, Sucov H.M. and Tsukamoto H. (2009). Mesenchymal origin of hepatic stellate cells, submesothelial cells, and perivascular mesenchymal cells duringmouse liver development. Hepatology 49, 998-1011.
3. Asahina K., Zhou B., Pu W.T. and Tsukamoto H. (2011). Septum transversum-derived mesothelium gives rise to hepatic stellate cells and perivascular mesenchymal cells in developing mouse liver. Hepatology 53, 983-995.
4. Asawa S., Saito T., Satoh A., Ohtake K., Tsuchiya T., Okada H., Neilson E.G. and Gotoh M. (2007). Participation of bone marrow cells in biliary fibrosis after bile duct ligation. J. Gastroenterol. Hepatol. 22, 2001-2008.
5. Baba S., Fujii H., Hirose T., Yasuchika K., Azuma H., Hoppo T., Naito M., Machimoto T. and Ikai I. (2004). Commitment of bone marrow cells to hepatic stellate cells in mouse. J. Hepatol. 40, 255-260.
6. Bataller R., Gasull X., Gines P., Hellemans K., Görbig M.N, Nicolás J.M., Sancho-Bru P., De Las Heras D., Gual A., Geerts A., Arroyo V. and Rodés J. (2001). In vitro and in vivo activation of rat hepatic stellate cells results in de novo expression of L-type voltageoperated calcium channels. Hepatology 33, 956-962.
7. Beaussier M., Wendum D., Schiffer E., Dumont S., Rey C., Lienhart A. and Housset C. (2007). Prominent contribution of portal mesenchymal cells to liver fibrosis in ischemic and obstructive cholestatic injuries. Lab. Invest. 87, 292-303.
8. Boulter L., Govaere O., Bird T.G., Radulescu S., Ramachandran P., Pellicoro A., Ridgway R.A., Seo S.S., Spee B., Van Rooijen N., Sansom O.J., Iredale J.P., Lowell S., Roskams T. and Forbes S.J. (2012). Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nat. Med. 18, 572-579.
9. Busletta C., Novo E., Valfrè di Bonzo L., Povero D., Paternostro C., Ievolella M., Mareschi K., Ferrero I., Cannito S., Compagnone A., Bandino A., Colombatto S. and Parola M. (2011). Dissection of the biphasic nature of hypoxia-induced motogenic action in bone marrow-derived human mesenchymal stem cells. Stem Cells 29, 952-963.
10. Cannito S., Novo E., Valfrè di Bonzo L., Busletta C., Colombatto S. and Parola M. (2010). Epithelial-mesenchymal transition: from molecular mechanisms, redox regulation to implications in human health and disease. Antioxid. Redox Signal. 12, 1383-1430.
11. Cannito S., Paternostro C., Busletta C., Bocca C., Colombatto S., Miglietta A., Novo E. and Parola M. (2014). Hypoxia, hypoxiainducible factors and fibrogenesis in chronic liver diseases. Histol. Histopathol. 29, 33-44.
12. Cassiman D., Libbrecht L., Desmet V., Denef C. and Roskams T (2002). Hepatic stellate cell/myofibroblast subpopulations in fibrotic human and ratlivers. J. Hepatol. 36, 200-209.
13. Cassiman D., Barlow A., Vander Borght S., Libbrecht L. and Pachnis V. (2006). Hepaticstellate cells do not derive from the neural crest. J. Hepatol. 44, 1098-1104.
14. Chen Y., Zheng S., Qi D., Zheng S., Guo J., Zhang S. and Weng Z. (2012). Inhibition of Notch signaling by a γ-secretase inhibitor attenuates hepatic fibrosis in rats. PloS One 7 e46512.
15. Chiaramonte M.G., Donaldson D.D., Cheever A.W. and Wynn T.A. (1999). An IL-13 inhibitor blocks the development of hepatic fibrosisduring a T-helper type 2-dominated inflammatory response. J. Clin. Invest. 104, 777-785.
16. Choi S.S. and Diehl A.M. (2009). Epithelial-to-mesenchymal transitions in the liver. Hepatology 50, 2007-2013.
17. Choi S.S., Syn W.K., Karaca G.F., Omenetti A., Moylan C.A., Witek R.P., Agboola K.M., Jung Y., Michelotti G.A. and Diehl A.M. (2010). Leptin promotes the myofibroblastic phenotype in hepatic stellate cells by activating the Hedgehog pathway. J. Biol. Chem. 285, 36551-36560.
18. Chu A.S., Diaz R., Hui J.-J., Yanger K., Zong Y., Alpini G., Stanger B.Z. and Wells R.G. (2011). Lineage tracing demonstrates no evidence of cholangiocyte epithelial-to-mesenchymal transition in murine models of hepatic fibrosis. Hepatology 53, 1685-1695.
19. Clouston A.D., Powell E.E., Walsh M.J., Richardson M.M., Demetris A.J. and Jonsson J.R. (2005). Fibrosis correlates with a ductular reaction in hepatitis C: roles of impaired replication, progenitor cells and steatosis. Hepatology 41, 809-818.
20. Clouzeau-Girard H., Guyot C., Combe C., Moronvalle-Halley V., Housset C., Lamireau T., Rosenbaum J. and Desmoulière A. (2006). Effects of bile acids on biliary epithelial cell proliferation and portal fibroblast activation using rat liver slices. Lab. Invest. 86, 275-285.
21. Dalakas E., Newsome P.N., Boyle S., Brown R., Pryde A., McCall S., Hayes P.C., Bickmore W.A., Harrison D.J. and Plevris J. (2010).Bone marrow stem cells contribute to alcohol liver fibrosis in humans. Stem Cells Dev. 19, 1417-1425.
22. Deleve L.D., Wang X. and Guo Y. (2008). Sinusoidal endothelial cells prevent rat stellate cell activation and promote reversion to quiescence. Hepatology 48, 920-930.
23. Dooley S., Hamzavi J., Ciuclan L., Godoy P., Ilkavets I., Ehnert S., Ueberham E., Gebhardt R., Kanzler S., Geier A., Breitkopf K., Weng H. and Mertens P.R. (2008). Hepatocyte-specific Smad7 expression attenuates TGF-beta-mediated fibrogenesis and protects against liver damage. Gastroenterology 135, 642-659.
24. Dranoff J.A. and Wells R.G. (2010). Portal fibroblasts: Underappreciated mediators of biliary fibrosis. Hepatology 51, 1438-1444.
25. Duffield J.S., Forbes S.J., Constandinou C.M., Clay S., Partolina M., Vuthoori S., Wu S., Lang R. and Iredale J.P. (2005). Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J. Clin. Invest. 115, 56-65.
26. Enzan H., Himeno H., Hiroi M., Kiyoku H., Saibara T. and Onishi S. (1997). Development of hepatic sinusoidal structure with special reference to the Ito cells. Microsc. Res. Tech. 39, 336-349.
27. Fabris L., Cadamuro M., Guido M., Spirli C., Fiorotto R., Colledan M., Torre G., Alberti D., Sonzogni A., Okolicsanyi L. and Strazzabosco M. (2007). Analysis of liver repair mechanisms in Alagille syndrome and biliaryatresia reveals a role for notch signaling. Am. J. Pathol. 171, 641-653.
28. Fallowfield J.A., Mizuno M., Kendall T.J., Constandinou C.M., Benyon R.C., Duffield J.S. and Iredale J.P. (2007). Scar associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J. Immunol. 178, 5288-5295.
29. Fernández M., Semela D., Bruix J., Colle I., Pinzani M. and Bosch J. (2009). Angiogenesis in liver disease. J. Hepatol. 50, 604-620.
30. Forbes S.J. and Parola M. (2011). Liver fibrogenic cells. Best Pract. Res. Clin. Gastroenterol. 25, 207-218.
31. Forbes S.J. and Newsome P.N. (2012). New horizons for stem cell therapy in liver disease. J. Hepatol. 56, 496-499.
32. Forbes S.J., Russo F., Rey V., Burra P., Rugge M., Wright N.A. and Alison M.R. (2004). A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis. Gastroenterology 126, 955-963.
33. Friedman S.L. (2008a). Mechanisms of hepatic fibrogenesis. Gastroenterology 134, 1655-1669.
34. Friedman S.L. (2008b). Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol. Rev. 88, 125-172.
35. Funyu J., Mochida S., Inao M., Matsui A. and Fujiwara K. (2001). VEGF can act as vascular permeability factor in the hepatic sinusoids through up regulation of porosity of endothelial cells. Biochem. Biophy.s Res. Commun. 280, 481-485.
36. Fujimiya T., Liu J., Kojima H., Shirafuji S., Kimura H. and Fujimiya M. (2009). Pathological roles of bone marrow-derived stellate cells in a mouse model of alcohol induced fatty liver. Am. J. Physiol. Gastrointest. Liver Physiol. 297, G451-460.
37. Gao B. and Radaeva S. (2013). Natural killer and natural killer T cells in liver fibrosis. Biochim. Biophys. Acta 1832, 1061-1069.
38. Geerts A. (2001). History, heterogeneity, developmental biology and functions of quiescent hepatic stellate cells. Semin. Liver Dis. 21, 311-335.
39. Greenbaum L.E. and Wells R.G. (2011). The role of stem cells in liver repair and fibrosis. Int. J. Biochem. Cell Biol. 43, 222-229.
40. Gur C., Doron S., Kfir-Erenfeld S., Horwitz E., Abu-Tair L., Safadi R. and Mandelboim O. (2012). NKp46-mediated killing ofhuman and mouse hepatic stellate cells attenuates liver fibrosis. Gut 61, 885-893.
41. Hoppo T., Fujii H., Hirose T., Yasuchika K., Azuma H., Baba S., Naito M., Machimoto T. and Ikai I. (2004). Thy1-positive mesenchymal cells promote the maturation of CD49f-positive hepatic progenitor cells in the mouse fetal liver. Hepatology 39, 1362-1370.
42. Houlihan D.D. and Newsome P.N. (2008). Critical review of clinical trials of bone marrow stem cells in liver disease. Gastroenterology 135, 438-450.
43. Higashiyama R., Moro T., Nakao S., Mikami K., Fukumitsu H., Ueda Y., Ikeda K., Adachi E., Bou-Gharios G., Okazaki I. and Inagaki Y. (2009). Negligible contribution of bone marrow-derived cells to collagen production during hepatic fibrogenesis in mice. Gastroenterology 137, 1459-1466.
44. Iredale J., Benyon R., Pickering J., McCullen M., Northrop M., Pawley S., Hovell C. and Arthur M. (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.
45. Iredale J.P., Thompson A. and Henderson N.C. (2013). Extracellular matrix degradation in liver fibrosis. Biochemistry and regulation. Biochim. Biophys. Acta 1832, 876-883.
46. Iwaisako K., Brenner D.A. and Kisseleva T. (2012). What’s new in liver fibrosis? The origin of myofibroblasts in liver fibrosis. J. Gastroenterol. Hepatol. 27 (suppl 2), 65-68.
47. Iwakiri Y., Shah V. and Rockey D.C. (2014). Vascular pathobiology in chronic liver disease and cirrhosis—current status and future directions. J. Hepatol. 61, 912-924.
48. Jarnagin W.R., Rockey D.C., Koteliansky V.E., Wang S.S. and Bissell D.M. (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, 2037-2048.
49. Kalluri R. and Weinberg R.A. (2009). The basics of epithelialmesenchymal transition. J. Clin. Invest. 119, 1420–1428.
50. Karlmark K.R., Weiskirchen R., Zimmermann H.W., Gassler N., Ginhoux F., Weber C., Merad M., Luedde T., Trautwein C. and Tacke F. (2009). Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 50, 261-274.
51. Katz S.C., Ryan K., Ahmed N., Plitas G., Chaudhry U.I., Kingham T.P., Naheed S., Nguyen C., Somasundar P., Espat N.J., Junghans R.P. and Dematteo R P. (2011). Obstructive jaundice expands intrahepatic regulatory T cells, which impair liver T lymphocyte function but modulate liver cholestasis and fibrosis. J. Immunol. 187, 1150-1156.
52. Kawada N., Tran-Thi T.A., Klein H. and Decker K. (1993). The contraction of hepatic stellate (Ito) cells stimulated with vasoactive substances. Possible involvement of endothelin 1 and nitric oxide in the regulation of the sinusoidal tonus. Eur. J. Biochem. 213, 815-823.
53. Kawada N., Kuroki T., Kobayashi K., Inoue M., Kaneda K. and Decker K. (1995). Action of endothelins on hepatic stellate cells. J. Gastroenterol. 30, 731-738.
54. Kendall T.J., Hennedige S., Aucott R.L., Hartland S.N., Vernon M.A., Benyon R.C. and Iredale J.P. (2009). Neurotrophin receptor signaling regulates hepatic myofibroblast proliferation and apoptosis in recovery from rodent liver fibrosis. Hepatology 49, 901-910.
55. Kinnman N. and Housset C. (2002). Peribiliary myofibroblasts in biliary type liver fibrosis. Front. Biosci. 7, d496-d503.
56. Kisseleva T., Uchinami H., Feirt N., Quintana-Bustamante O., Segovia J.C., Schwabe R.F. and Brenner D.A. (2006). Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis. J. Hepatol. 45, 429-438.
57. Krizhanovsky V., Yon M., Dickins R.A., Hearn S., Simon J., Miething C., Yee H., Zender L. and Lowe S.W. (2008). Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657-667.
58. Kubota H., Yao H.L. and Reid L.M. (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, 2339-2349.
59. Laleman W., Van Landeghem L., Severi T., Vander Elst I., Zeegers M., Bisschops R., Van Pelt J., Roskams T., Cassiman D., Fevery J. and Nevens F. (2007). Both Ca2+-dependent and –independent pathways are involved in rat hepatic stellate cell contraction and intrahepatic hyperresponsiveness to methoxamine. Am. J. Physiol. Gastrointest. Liver Physiol. 292, G556-G564.
60. Langer D.A., Das A., Semela D., Kang-Decker N., Hendrickson H., Bronk S.F., Katusic Z.S., Gores G.J. and Shah V.H. (2008). Nitric oxide promotes caspase-independent hepatic stellate cell apoptosis through the generation of reactive oxygen species. Hepatology 47, 1983-1993.
61. Langhans B., Krämer B., Louis M., Nischalke H.D., Hüneburg R., Staratschek-Jox A., Odenthal M., Manekeller S., Schepke M., Kalff J., Fischer H.P., Schultze J.L. and Spengler U. (2013). Intrahepatic IL-8 producing Foxp3+CD4+ regulatory T cells and fibrogenesis in chronic hepatitis C. J. Hepatol. 59, 229-235.
62. Lemoinne S., Cadoret A., El Mourabit H., Thabut D. and Housset C. (2013). Origins and functions of liver myofibroblasts. Biochim. Biophys. Acta 1832, 948-954.
63. Liu X., Li J., Xiong J., Li M., Zhang Y. and Zheng Q. (2012). Notchdependent expression of epithelial-mesenchymal transition markers in cholangiocytes after liver transplantation. Hepatol. Res. 42, 1024-1038.
64. Lorenzini S., Bird T.G., Boulter L., Bellamy C., Samuel K., Aucott R., Clayton E., Andreone P., Bernardi M., Golding M., Alison M.R., Iredale J.P. and Forbes S.J. (2010). Characterization of a stereotypical cellular and extracellular adult LPC niche in rodents and diseased human liver. Gut 59, 645-654.
65. Mallat A. and Lotersztain S. (2013). Cellular mechanisms of tissue fibrosis. 5. Novel insights into liver fibrosis. Am. J. Physiol., Cell Physiol. 305, C789-C799.
66. Mallat A., Preaux A.M., Serradeil-Le G., Raufaste D., Gallois C., Brenner D.A., Bradham C., Maclouf J., Iourgenko V., Fouassier L., Dhumeaux D., Mavier P. and Lotersztajn S. (1996). Growth inhibitory properties of endothelin-A in activated human stellate cells: a cyclic adenosine monophosphatemediated pathway. J. Clin. Invest. 98, 2771-2778.
67. Marra F. and Tacke F. (2014). Roles for chemokines in liver disease. Gastroenterology 147, 577-594.
68. May D., Djonov V., Zamir G., Bala M., Safadi R., Sklair-Levy M. and Keshet E. (2011). A transgenic model for conditional induction and rescue of portal hypertension reveals a role of VEGF-mediated regulation of sinusoidal fenestrations. PLoS One 6, e21478.
69. Mederacke I., Hsu C.C., Troeger J.S., Huebener P., Mu X., Dapito D.H., Pradere J.P. and Schwabe R.F. (2013). Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat. Commun. 4, 2823.
70. Medina J., Arroyo A.G., Sánchez-Madrid F. and Moreno-Otero R. (2004). Angiogenesis in chronic inflammatory liver disease. Hepatology 39, 1185-1195.
71. Melhem A., Muhanna N., Bishara A., Alvarez C.E., Ilan Y., Bishara T., Horani A., Nassar M., Friedman S.L. and Safadi R. (2006). Antifibrotic activity of NK cells in experimental liver injury through killing of activated HSC. J. Hepatol. 45, 60-71.
72. Melton A.C., Datta A. and Yee H.F. Jr (2006). [Ca2+]i-independent contractile force generation by rat hepatic stellate cells in response to endothelin-1. Am. J. Physiol. Gastroint. Liver Physiol. 290, G7-13.
73. Meng F., Wang K., Aoyama T., Grivennikov S.I., Paik Y., Scholten D., Cong M., Iwaisako K., Liu X., Zhang M., Osterreicher C.H., Stickel F., Ley K., Brenner D.A. and Kisseleva T. (2012). Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology 143, 765-776. e1-3.
74. Michelotti G.A., Xie G., Swiderska M., Choi S.S., Karaca G., Krüger L., Premont R., Yang L., Syn W.K., Metzger D. and Diehl A.M. (2013). Smoothened is a master regulator of adult liver repair. J. Clin. Invest. 123, 2380-2394.
75. Moon J.-K., Welch T.P., Gonzalez F.J. and Copple B.L. (2009). Reduced liver fibrosis in hypoxia-inducible factor- 1alpha-deficient mice. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G582-592.
76. Muhanna N., Doron S., Wald O., Horani A., Eid A., Pappo O., Friedman S.L and Safadi R. (2008). Activation of hepatic stellate cells after phagocytosis of lymphocytes: a novel pathway of fibrogenesis. Hepatology 48, 963-977.
77. Muhanna N., Abu Tair L., Doron S., Amer J., Azzeh M., Mahamid M., Friedman S. and Safadi R. (2011). Amelioration of hepatic fibrosis by NK cell activation. Gut 60, 90-98.
78. Novo E. and Parola M. (2008). Redox mechanisms in hepatic chronic wound healing and liver fibrogenesis. Fibrogenesis Tissue Repair 1, 5.
79. Novo E., Marra F., Zamara E., Valfrè di Bonzo L., Caligiuri A., Cannito S., Antonaci C., Colombatto S., Pinzani M. and Parola M. (2006a). Dose dependent and divergent effects of superoxide anion on cell death, proliferation, and migration of activated human hepatic stellate cells. Gut 55, 90-97.
80. Novo E., Marra F., Zamara E., Valfrè di Bonzo L., Monitillo L., Cannito S., Petrai I., Mazzocca A., Bonacchi A., De Franco R.S., Colombatto S., Autelli R., Pinzani M. and Parola M. (2006b). Overexpression of Bcl-2 by activated human hepatic stellate cells: resistance to apoptosis as a mechanism of progresive hepatic fibrogenesis in humans. Gut 55, 1174-1182.
81. Novo E., Cannito S., Zamara E., Valfrè di Bonzo L., Caligiuri A., Cravanzola C., Compagnone A., Colombatto S., Marra F., Pinzani M. and Parola M. (2007). Proangiogenic cytokines as hypoxiadependent factors stimulating migration of human hepatic stellate cells. Am. J. Pathol. 170, 1942-1953.
82. Novo E., Busletta C., Valfrè di Bonzo L., Povero D., Paternostro C., Mareschi K., Ferrero I., David E., Bertolani C., Caligiuri A., Cannito S., Tamagno E., Compagnone A., Colombatto S., Marra F., Fagioli F., Pinzani M. and Parola M. (2011). Intracellular reactive oxygen species are required for directional migration of resident and bone marrow-derived hepatic profibrogenic cells. J. Hepatol. 54, 964-974.
83. Novo E., Povero D., Busletta C., Paternostro C., Valfrè di Bonzo L., Cannito S., Compagnone A., Bandino A., Marra F., Colombatto S., Pinzani M. and Parola M. (2012). The biphasic nature of hypoxiainduced directional migration of activated human hepatic stellate cells. J. Pathol. 226, 588-597.
84. Novo E., Cannito S., Paternostro C., Bocca C., Miglietta A. and Parola M. (2014). Cellular and molecular mechanisms in liver fibrogenesis. Arch. Biochem. Biophys. 548, 20-37.
85. Oakley F., Teoh V., Ching A.S.G., Bataller R., Colmenero J., Jonsson J.R., Eliopoulos A.G., Watson M.R., Manas D. and Mann D.A. (2009). Angiotensin II activates I kappaB kinase phosphorylation of RelA at Ser 536 to promote myofibroblast survival and liver fibrosis. Gastroenterology 136, 2334- 2344.
86. Omenetti A., Yang L., Li Y.X., McCall S.J., Jung Y., Sicklick J.K., Huang J., Choi S., Suzuki A. and Diehl A.M. (2007). Hedgehog-mediated mesenchymal-epithelial interactions modulate hepatic response to bile duct ligation. Lab. Invest. 87, 499-514.
87. Österreicher C.H., Penz-Österreicher M., Grivennikov S.I., Guma M., Koltsova E.K., Datz C., Sasik R., Hardiman G., Karin M. and Brenner D.A. (2011). Fibroblast-specific protein 1 identifies an inflammatory subpopulation of macrophages in the liver. Proc. Natl. Acad. Sci. USA 108, 308-313.
88. Parola M. and Marra F. (2011). Adipokines and redox signaling: impact on fatty liver disease. Antioxid. Redox Signal. 15, 461-483.
89. Parola M., Marra F. and Pinzani M. (2008). Myofibroblast - like cells and liver fibrogenesis: emerging concepts in a rapidly moving scenario. Mol. Aspects Med. 29, 59-67.
90. Pellicoro A., Ramachandran P., Iredale J.P. and Fallowfield J.A. (2014). Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat. Rev. Immunol. 14, 181-94.
91. Pinzani M. and Marra F. (2001). Cytokine receptor and signalling in hepatic stellate cells. Semin. Liver Dis. 21, 397-417.
92. Pinzani M. and Rombouts K. (2004). Liver fibrosis: from the bench to clinical targets. Dig. Liver Dis. 36, 231-242.
93. Pinzani M., Failli P., Ruocco C., Casini A., Milani S., Baldi E., Giotti A. and Gentilini P. (1992). Fat-storing cells as liver-specific pericytes: Spatial dynamics of agonist-stimulated intracellular calcium transients. J. Clin. Invest. 90, 642-646.
94. Pinzani M., Milani S., De Franco R., Grappone C., Caligiuri A., Gentilini A., Tosti-Guerra C., Maggi M., Failli P., Ruocco C. and Gentilini P. (1996). Endothelin 1 is overexpressed in human cirrhotic liver and exerts multiple effects on activated hepatic stellate cells. Gastroenterology 110, 534-548.
95. Povero D., Busletta C., Novo E., Valfrè di Bonzo L., Cannito S., Paternostro C. and Parola M. (2010). Liver fibrosis: a dynamic and potentially reversible process. Histol. Histopathol. 25, 1075-1091.
96. Radaeva S., Sun R., Jaruga B., Nguyen V.T., Tian Z. and Gao B. (2006). Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners. Gastroenterology 130, 435-452.
97. Radaeva S., Wang L., Radaev S., Jeong W.I., Park O. and Gao B. (2007). Retinoic acid signalling sensitizes hepatic stellate cells to NK cell killing via upregulation of NK cell activating ligand RAE1. Am. J. Physiol. Gastrointest. Liver Physiol. 293, G809-816.
98. Ramachandran P., Pellicoro A., Vernon M.A., Boulter L., Aucott R.L., Ali A., Hartland S.N., Snowdon V.K., Cappon A., Gordon-Walker T.T., Williams M.J., Dunbar D.R., Manning J.R., van Rooijen N., Fallowfield J.A., Forbes S.J. and Iredale J.P. (2012). Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc. Natl. Acad. Sci. USA 109, E3186-E3195.
99. Reynaert H., Thompson M.G., Thomas T. and Geerts A. (2002). Hepatic stellate cells: role in microcirculation and pathophysiology of portal hypertension. Gut 50, 571-581.
100. Richardson M.M., Jonsson J.R., Powell E.E., Brunt E.M., Neuschwander-Tetri B.A., Bhathal P.S., Dixon J.B., Weltman M.D., Tilg H., Moschen A.R., Purdie D.M., Demetris A.J. and Clouston A.D. (2007). Progressive fibrosis in nonalcoholic steatohepatitis: association with altered regeneration and a ductular reaction. Gastroenterology 133, 80-90.
101. Rockey D.C. (2001). Hepatic blood flow regulation by stellate cells in normal and injured liver. Semin. Liver Dis. 21, 337-349.
102. Rockey D.C. (2003). Vascular mediators in the injured liver. Hepatology, 37, 4-12.
103. Rockey D.C. and Weisiger R.A. (1996). Endothelin induced contractility of stellate cells from normal and cirrhotic rat liver: implications for regulation of portal pressure and resistance. Hepatology 24, 233-240.
104. Rockey D.C., Boyles J.K., Gabbiani G. and Friedman S.L. (1992a). Rat hepatic lipocytes express smooth muscle actin upon activation in vivo and in culture. J. Submicrosc. Cytol. Pathol. 24, 193-203.
105. Rockey D.C., Maher J.J., Jarnagin W.R., Gabbiani G. and Friedman S.L. (1992b). Inhibition of rat epatic lipocyte activation in culture by interferon-gamma. Hepatology 16,776-784.
106. Rockey D.C., Fouassier L., Chung J.J., Carayon A., Vallee P., Rey C. and Housset C. (1998). Cellular localization of endothelin-1 and increased production in liver injury in the rat: potential for autocrine and paracrine effects on stellate cells. Hepatology 27, 472-480.
107. Rosselli M., MacNaughtan J., Jalan R. and Pinzani M. (2013). Beyond scoring: a modern interpretation of disease progression in chronic liver disease. Gut 62, 1234-1241.
108. Russo F.P., Alison M.R., Bigger B.W., Amofah E., Florou A., Amin F., Bou-Gharios G., Jeffery R., Iredale J.P. and Forbes S.J. (2006). The bone marrow functionally contributes to liver fibrosis. Gastroenterology 130, 1807-1821.
109. Saab S., Tam S.P., Tran B.N., Melton A., Tangkijvanich P., Wong H. and Yee H. (2002). Myosin mediates contractile force generation by hepatic stellate cells in response to endothelin-1. J. Biomed. Sci. 9, 607-612.
110. Scholten D., Osterreicher C.H., Scholten A., Iwaisako K., Gu G., Brenner D.A. and Kisseleva T. (2010) Genetic labeling does not detect epithelial-to-mesenchymal transition of cholangiocytes in liver fibrosis in mice. Gastroenterology 139, 987-998.
111. Schuppan D. and Kim Y.O. (2013). Evolving therapies for liver fibrosis. J. Clin. Invest. 123,1887-1901.
112. Schuppan D. and Pinzani M. (2012). Anti-fibrotic therapy: lost in translation? J. Hepatol. 56 (Suppl. 1), S66-74.
113. Shah V., Haddad F.G., Garcia-Cardena G., Frangos J.A., Mennone A., Groszmann R.J. and Sessa W.C. (1997). Liver sinusoidal endothelial cells are responsible for nitric oxide modulation of resistance in the hepatic sinusoids. J. Clin. Invest. 100, 2923-2930.
114. Shah V., Toruner M., Haddad F., Cadelina G., Papapetropoulos A., Choo K., Sessa W.C. and Groszmann R.J. (1999). Impaired endothelial nitric oxide synthase activity associated with enhanced caveolin binding in experimental cirrhosis in the rat. Gastroenterology 117, 1222-1228.
115. Shi Z., Wakil A.E. and Rockey D.C. (1997). Strain-specific differences in mouse hepatic wound healing are mediated by divergent T helper cytokine responses. Proc. Natl. Acad. Sci. USA 94, 10663-10668.
116. Smith K. (2013). Liver disease: Kupffer cells regulate the progression of ALD and NAFLD. Nat. Rev. Gastroenterol. Hepatol. 10, 503.
117. Suzuki K., Tanaka M., Watanabe N., Saito S., Nonaka H. and Miyajima A. (2008). p75 Neurotrophin receptor is a marker for precursors of stellate cells and portal fibroblasts in mouse fetal liver. Gastroenterology 135, 270-281.
118. Tacke F. and Zimmermann H.W. (2014). Macrophage heterogeneity in liver injury and fibrosis. J. Hepatol. 60, 1090-1096.
119. Taimr P., Higuchi H., Kocova E., Rippe R.A., Friedman S. and Gores G.J. (2003). Activated stellate cells express the TRAIL receptor- 2/death receptor-5 and undergo TRAIL mediated apoptosis. Hepatology 37, 87-95.
120. Taura K., De Minicis S., Seki E., Hatano E., Iwaisako K., Osterreicher C.H., Kodama Y., Miura K., Ikai I., Uemoto S. and Brenner D.A. (2008). Hepatic stellate cells secrete angiopoietin 1 that induces angiogenesis in liver fibrosis. Gastroenterology 135, 1729-1738.
121. Taura K., Miura K., Iwaisako K., Osterreicher C.H., Kodama Y., PenzOsterreicher M. and Brenner D.A. (2010). Hepatocytes do not undergo epithelial-mesenchymal transition in liver fibrosis in mice. Hepatology 51, 1027-1036.
122. Troeger J.S., Mederacke I., Gwak G.Y., Dapito D.H., Mu X., Hsu C.C., Pradere J.P., Friedman R.A. and Schwabe R.F. (2012). Deactivation of hepatic stellate cells during liver fibrosis resolution in mice. Gastroenterology 143, 1073-1083.
123. Tuchweber B., Desmouliere A., Bochaton-Piallat M.L., Rubbia-Brandt L. and Gabbiani G. (1996). Proliferation and phenotypic modulation of portal fibroblasts in the early stages of cholestatic fibrosis in the rat. Lab. Invest. 74, 265-278.
124. Turner J.D., Jenkins G.R., Hogg K.G., Aynsley S.A., Paveley R.A., Cook P.C., Coles M.C. and Mountford A.P. (2011). CD4+CD25+ regulatory cells contribute to the regulation of colonic TH2 granulomatous pathology caused by schistosome infection. PLoS Negl. Trop. Dis. 5:e1269.
125. Valfrè di Bonzo L., Ferrero I., Cravanzola C., Mareschi K., Rustichell D., Novo E., Sanavio F., Cannito S., Zamara E., Bertero M., Davit A., Francica S., Novelli F., Colombatto S., Fagioli F. and Parola M. (2008). Human mesenchymal stem cells as a two-edged sword in hepatic regenerative medicine: engraftment and hepatocyte differentiation versus profibrogenic potential. Gut 57, 223-231.
126. Valfrè di Bonzo L., Novo E., Cannito S., Busletta C., Paternostro C., Povero D. and Parola M. (2009). Angiogenesis and liver fibrogenesis. Histol. Histopathol. 24, 1323-1341.
127. Van Hul N.K., Abarca-Quinones J., Sempoux C., Horsmans Y. and Leclercq I.A. (2009). Relation between liver progenitor cell expansion and extracellular matrix deposition in a CDE-induced murine model of chronic liver injury. Hepatology 49, 1625-1635.
128. Wake K. (1980). 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. Intern. Rev. Cytol. 66, 303-353.
129. Wells R.G. (2014). The portal fibroblast: not just a poor man's stellate cell. Gastroenterology 147, 41-47.
130. Wells R.G., Kruglov E. and Dranoff J.A. (2004). Autocrine release of TGF-beta by portal fibroblasts regulates cell growth. FEBS Lett. 559, 107-110.
131. Wright M.C., Issa R., Smart D.E., Trim N., Murray G.I., Primrose J.N., Arthur M.J., Iredale J.P. and Mann D.A. (2001). Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cells and enhances the resolution of liver fibrosis in rats. Gastroenterology 121, 685-698.
132. Wynn T.A. (2004). Fibrotic disease and the Th1/Th2 paradigm. Nat. Rev. Immunol. 4, 583-594.
133. Wynn T.A., Cheever A.W., Jankovic D., Poindexter R.W., Caspar P., Lewis F.A. and Sher A. (1995). An IL-12-based vaccination method for preventing fibrosis induced by schistosome infection. Nature 376, 594-596.
134. Xia J.L., Dai C., Michalopoulos G.K. and Liu Y. (2006). Hepatocyte growth factor attenuates liver fibrosis induced by bile duct ligation. Am. J. Pathol. 168, 1500-1512.
135. Xie G. and Diehl A.M. (2013). Evidence for and against epithelial-tomesenchymal transition in the liver. Am. J. Physiol. Gastrointest. Liver Physiol. 305, G881–G890.
136. Xie G., Karaca G., Swiderska-Syn M., Michelotti G.A., Kruger L., Chen Y., Premont R.T., Choi S.S. and Diehl A.M. (2013). Cross-talk between Notch and Hedgehog regulates hepatic stellate cell fate in mice. Hepatology 58, 1801-1813.
137. Yanagisawa M., Kurihara H., Kimura S., Tomobe Y., Kobayashi M., Mitsui Y., Yazaki Y., Goto K. and Masaki T. (1988). A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332, 411-415.
138. Yang L., Jung Y., Omenetti A., Witek R.P., Choi S., Vandongen H.M., Huang J., Alpini G.D. and Diehl A.M. (2008). Fate-mapping evidence that hepatic stellate cells are epithelial progenitors in adult mouse livers. Stem Cells 26, 2104-2113.
139. Yee H.F. (2001). Ca2+ and rho signaling pathways: two paths to hepatic stellate cell contraction. Hepatology 33, 1007-1008.
140. Yin C., Evason K.J., Asahina K. and Stainier D.Y. (2013). Hepatic stellate cells in liver development, regeneration, and cancer. J. Clin. Invest. 123, 1902-1910.
141. Yokomori H., Oda M., Yoshimura K., Nagai T., Ogi M., Nomura M. and Ishii H. (2003). Vascular endothelial growth factor increases fenestral permeability in hepatic sinusoidal endothelial cells. Liver Int. 23, 467-475.
142. Zaret K.S. (2002). Regulatory phases of early liver development: paradigms of organogenesis. Nat. Rev. Genet. 3, 499-512.
143. Zeisberg M., Yang C., Martino M., Duncan M.B., Rieder F., Tanjore H. and Kalluri R. (2007). Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J. Biol. Chem. 282, 23337-23347.
144. Zhang D.Y. and Friedman S.L. (2012). Fibrosis-dependent mechanisms of hepatocarcinogenesis. Hepatology 56, 769-775. Accepted April 21, 2015