Progenitor Cells in Diseased Human Liver

Tania A. Roskams; Louis Libbrecht; Valeer J. Desmet

doi:10.1055/s-2004-815564

Seminars in Liver Disease, Table of Contents

Semin Liver Dis 2003; 23(4): 385-396
DOI: 10.1055/s-2004-815564

Progenitor Cells in Diseased Human Liver

Tania A. Roskams^1,2 , Louis Libbrecht² , Valeer J. Desmet²

¹Professor in Pathology and Head, Laboratory of Morphology and Molecular Pathology, University of Leuven, Leuven, Belgium
²Liver Research Unit, Laboratory of Morphology and Molecular Pathology, University of Leuven, Leuven, Belgium

Abstract

ABSTRACT

Hepatic progenitor cells are immature epithelial cells that reside in the smallest ramifications of the biliary tree in human liver. These cells are capable of differentiating toward the biliary and the hepatocytic lineages and represent the human counterpart of the oval cells in murine liver. An increased number of progenitor cells (referred to as “activation”) and differentiation of the same toward hepatocytes or bile duct epithelial cells, or both, is a component of virtually all human liver diseases. The extent of progenitor cell activation and the direction of differentiation are correlated with the severity of the disease and the type of mature epithelial cell (hepatocyte or bile duct epithelial cell), respectively, that is damaged. Analogous to findings in animal models of hepatocarcinogenesis, human hepatic progenitor cells most likely can give rise to hepatocellular carcinoma. The factors that govern human hepatic progenitor cell activation and differentiation are beginning to be identified.

KEYWORDS

Hepatic progenitor cells - oval cells - human liver diseases - progenitor cell activation and differentiation - hepatocarcinogenesis

Full Text

References

REFERENCES

1 Fausto N. Liver stem cells. In: Arias IM, Boyer JL, Fausto N, et al, eds. The Liver: Biology and Pathobiology, 3rd ed New York: Raven Press 1994: 1501-1518
2 Opie E L. The pathogenesis of tumors of the liver produced by butter yellow. J Exp Med . 1944; 80 231-246
3 Farber E. Similarities in the sequence of early histologic changes induced in the liver of the rat by ethionine, 2-acetylaminofluorene, and 3′-methyl-4-dimethylaminoazobenzene. Cancer Res . 1956; 16 142-148
4 Grisham J W, Hartroft W S. Morphologic identification by electronmicroscopy of oval cells in experimental hepatic degeneration. Lab Invest . 1961; 10 317-332
5 Fausto N. Hepatocyte differentiation and liver progenitor cells. Curr Opin Cell Biol . 1990; 2 1036-1042
6 Sell S. Is there a liver stem cell?. Cancer Res . 1990; 50 3811-3815
7 Wilson J W, Leduc E H. Role of cholangioles in restoration of the liver of the mouse after dietary injury. J Pathol Bacteriol . 1958; 76 441-449
8 Lemire J M, Shiojiri N, Fausto N. Oval cell proliferation and the origin of small hepatocytes in liver injury induced by D-galactosamine. Am J Pathol . 1991; 139 535-552
9 Grisham J W. Cell types in long-term propagable cultures of rat liver. Ann N Y Acad Sci . 1980; 349 128-137
10 Germain L, Noel M, Gourdeau H, Marceau N. Promotion of growth and differentiation of rat ductular oval cells in primary culture. Cancer Res . 1988; 48 368-378
11 Lenzi R, Liu M H, Tarsetti F. et al . Histogenesis of bile duct-like cells proliferating during ethionine hepatocarcinogenesis. Evidence for a biliary epithelial nature of oval cells. Lab Invest . 1992; 66 390-402
12 Paku S, Schnur J, Nagy P, Thorgeirsson S S. Origin and structural evolution of the early proliferating oval cells in rat liver. Am J Pathol . 2001; 158 1313-1323
13 Germain L, Goyette R, Marceau N. Differential cytokeratin and alpha-fetoprotein expression in morphologically distinct epithelial cells emerging at the early stage of rat hepatocarcinogenesis. Cancer Res . 1985; 45 673-681
14 Hixson D C, Allison J P. Monoclonal antibodies recognizing oval cells induced in the liver of rats by N-2-fluorenylacetamide or ethionine in a choline-deficient diet. Cancer Res . 1985; 45 3750-3760
15 Dunsford H A, Karnasuta C, Hunt J M, Sell S. Different lineages of chemically induced hepatocellular carcinoma in rats defined by monoclonal antibodies. Cancer Res . 1989; 49 4894-4900
16 Dabeva M D, Alpini G, Hurston E, Shafritz D A. Models for hepatic progenitor cell activation. Proc Soc Exp Biol Med . 1993; 204 242-252
17 Dunsford H A, Sell S. Production of monoclonal antibodies to preneoplastic liver cell populations induced by chemical carcinogens in rats and to transplantable Morris hepatomas. Cancer Res . 1989; 49 4887-4893
18 Dabeva M D, Shafritz D A. Activation, proliferation, and differentiation of progenitor cells into hepatocytes in the D-galactosamine model of liver regeneration. Am J Pathol . 1993; 143 1606-1620
19 Mandache E, Vidulescu C, Gherghiceanu M, Dragomir P, Popescu L M. Neoductular progenitor cells regenerate hepatocytes in severely damaged liver: a comparative ultrastructural study. J Cell Mol Med . 2002; 6 59-73
20 Desmet V. Experimentele levercarcinogenese. Histochemische studie. Brussels: Arscia; 1963
21 Evarts R P, Nagy P, Marsden E, Thorgeirsson S S. A precursor-product relationship exists between oval cells and hepatocytes in rat liver. Carcinogenesis . 1987; 8 1737-1740
22 Tatematsu M, Kaku T, Medline A, Farber E. Intestinal metaplasia as a common option of oval cells in relation to cholangiofibrosis in liver of rats exposed to 2-acetylaminofluorene. Lab Invest . 1985; 52 354-362
23 Tsao M S, Grisham J W. Hepatocarcinomas, cholangiocarcinomas, and hepatoblastomas produced by chemically transformed cultured rat liver epithelial cells. Am J Pathol . 1987; 127 168-181
24 Evarts R P, Hu Z, Omori N. et al . Precursor-product relationship between oval cells and hepatocytes: comparison between tritiated thymidine and bromodeoxyuridine as tracers. Carcinogenesis . 1996; 17 2143-2151
25 Yasui O, Miura N, Terada K. et al . Isolation of oval cells from Long-Evans Cinnamon rats and their transformation into hepatocytes in vivo in the rat liver. Hepatology . 1997; 25 329-334
26 Alison M R, Poulsom R, Forbes S J. Update on hepatic stem cells. Liver . 2001; 21 367-373
27 Petersen B, Bowen W, Patrene K. et al . Bone marrow as a potential source of hepatic oval cells. Science . 1999; 284 1168-1170
28 Theise N, Badve S, Saxena R. et al . Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation. Hepatology . 2000; 31 235-240
29 Alison M R, Poulsom R, Jeffery R. et al . Hepatocytes from non-hepatic adult stem cells. Nature . 2000; 406 257
30 Korbling M, Katz R L, Khanna A. et al . Hepatocytes and epithelial cells of donor origin in recipients of peripheral-blood stem cells. N Engl J Med . 2002; 346 738-746
31 Theise N, Nimmakayalu M, Gardner R. et al . Liver from bone marrow in humans. Hepatology . 2000; 32 11-16
32 Wang X, Willenbring H, Akkari Y. et al . Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature . 2003; 422 897-901
33 Vassilopoulos G, Wang P R, Russell D W. Transplanted bone marrow regenerates liver by cell fusion. Nature . 2003; 422 901-904
34 Holden C. Stem cell research. Cells find destiny though merger. Science . 2003; 300 35
35 Libbrecht L, Roskams T. Hepatic progenitor cells in human liver diseases. Semin Cell Dev Biol . 2002; 13 389-396
36 Sell S. Comparison of liver progenitor cells in human atypical ductular reactions with those seen in experimental models of liver injury. Hepatology . 1998; 27 317-331
37 Roskams T, De Vos R, Van Eyken P. et al . Hepatic OV-6 expression in human liver disease and rat experiments: evidence for hepatic progenitor cells in man. J Hepatol . 1998; 29 455-463
38 Theise N D, Saxena R, Portmann B C. et al . The canals of Hering and hepatic stem cells in humans. Hepatology . 1999; 30 1425-1433
39 Haque S, Haruna Y, Saito K. et al . Identification of bipotential progenitor cells in human liver regeneration. Lab Invest . 1996; 75 699-705
40 Roskams T, De Vos R, van den Oord J J, Desmet V. Cells with neuroendocrine features in regenerating human liver. APMIS Suppl . 1991; 23 32-39
41 Gerber M A, Thung S N, Shen S, Stromeyer F W, Ishak K G. Phenotypic characterization of hepatic proliferation. Antigenic expression by proliferating epithelial cells in fetal liver, massive hepatic necrosis, and nodular transformation of the liver. Am J Pathol . 1983; 110 70-74
42 Lowes K N, Brennan B A, Yeoh G C, Olynyk J K. Oval cell numbers in human chronic liver diseases are directly related to disease severity. Am J Pathol . 1999; 154 537-541
43 Fujita M, Furukawa H, Hattori M. et al . Sequential observation of liver cell regeneration after massive hepatic necrosis in auxiliary partial orthotopic liver transplantation. Mod Pathol . 2000; 13 152-157
44 Libbrecht L, Desmet V, Van Damme B, Roskams T. Deep intralobular extension of human hepatic “progenitor cells” correlates with parenchymal inflammation in chronic viral hepatitis: can “progenitor cells” migrate?. J Pathol . 2000; 192 373-378
45 Sakamoto S, Yachi A, Anzai T, Wada T. AFP-producing cells in hepatitis and in liver cirrhosis. Ann N Y Acad Sci . 1975; 259 253-258
46 Xiao J C, Ruck P, Adam A, Wang T X, Kaiserling E. Small epithelial cells in human liver cirrhosis exhibit features of hepatic stem-like cells: immunohistochemical, electron microscopic and immunoelectron microscopic findings. Histopathology . 2003; 42 141-149
47 Ray M B, Mendenhall C L, French S W, Gartside P S. Bile duct changes in alcoholic liver disease. Liver . 1993; 13 36-45
48 Roskams T, Yang S Q, Koteish A. et al . Oxidative stress and oval cell accumulation in mice and humans with alcoholic and nonalcoholic fatty liver disease. Am J Pathol . 2003; 163 1301-1311
49 Hsia C C, Evarts R P, Nakatsukasa H, Marsden E R, Thorgeirsson S S. Occurrence of oval-type cells in hepatitis B virus-associated human hepatocarcinogenesis. Hepatology . 1992; 16 1327-1333
50 Libbrecht L, Craninx M, Nevens F, Desmet V, Roskams T. Predictive value of liver cell dysplasia for development of hepatocellular carcinoma in patients with non-cirrhotic and cirrhotic chronic viral hepatitis. Histopathology . 2001; 39 66-73
51 Libbrecht L, De Vos R, Cassiman D. et al . Hepatic progenitor cells in hepatocellular adenomas. Am J Surg Pathol . 2001; 25 1388-1396
52 Libbrecht L, Desmet V, Van Damme B, Roskams T. The immunohistochemical phenotype of dysplastic foci in human liver: correlation with putative progenitor cells. J Hepatol . 2000; 33 76-84
53 Alison M, Golding M, Lalani N el, Sarraf C. Wound healing in the liver with particular reference to stem cells. Philos Trans R Soc Lond B Biol Sci . 1998; 353 877-894
54 Bustos M, Sangro B, Alzuguren P. et al . Liver damage using suicide genes. A model for oval cell activation. Am J Pathol . 2000; 157 549-559
55 Sell S. The role of progenitor cells in repair of liver injury and in liver transplantation. Wound Repair Regen . 2001; 9 467-482
56 De Vos R, Desmet V. Ultrastructural characteristics of novel epithelial cell types identified in human pathological liver specimens with chronic ductular reaction. Am J Pathol . 1992; 140 1441-1450
57 Shafritz D A, Hadziyannis S J. Molecular Pathobiology of Persistent Hepatitis B Virus Infection in Relation to Chronic Liver Disease and Primary Hepatocellular Carcinoma. Baltimore: Williams and Wilkins; 1987
58 Saxena R, Theise N D, Crawford J M. Microanatomy of the human liver-exploring the hidden interfaces. Hepatology . 1999; 30 1339-1346
59 Alison M, Sarraf C. Hepatic stem cells. J Hepatol . 1998; 29 676-682
60 Alison M. Liver stem cells: a two compartment system. Curr Opin Cell Biol . 1998; 10 710-715
61 Roskams T, De Vos R, Desmet V. “Undifferentiated progenitor cells” in focal nodular hyperplasia of the liver. Histopathology . 1996; 28 291-299
62 Libbrecht L, Cassiman D, Desmet V, Roskams T. Expression of neural cell adhesion molecule in human liver development and in congenital and acquired liver diseases. Histochem Cell Biol . 2001; 116 233-239
63 Roskams T, Desmet V. Ductular reaction and its diagnostic significance. Semin Diagn Pathol . 1998; 15 259-269
64 Roskams T, De Vos R, van den Oord J J, Desmet V. Cells with neuroendocrine features in regenerating human liver. APMIS Suppl . 1991; 23 32-39
65 Xiao J C, Ruck P, Kaiserling E. Small epithelial cells in extrahepatic biliary atresia: electron microscopic and immunoelectron microscopic findings suggest a close relationship to liver progenitor cells. Histopathology . 1999; 35 454-460
66 Marceau N, Blouin M J, Germain L, Noel M. Role of different epithelial cell types in liver ontogenesis, regeneration and neoplasia. In Vitro Cell Dev Biol . 1989; 25 336-341
67 Fausto N, Campbell J S. The role of hepatocytes and oval cells in liver regeneration and repopulation. Mech Dev . 2003; 120 117-130
68 Karran S, Eagles C. Regeneration. Part 1 Physical aspects. In: Wright R, Alberti KG, Karran S, Millward-Sadler GH, eds. Liver and Biliary Disease Philadelphia: WB Saunders 1979: 197-210
69 Van Thiel H D, Gavaler J S, Kam I. et al . Rapid growth of an intact human liver transplanted into a recipient larger than the donor. Gastroenterology . 1987; 93 1414-1419
70 Phillips M J, Poucell S. Modern aspects of the morphology of viral hepatitis. Hum Pathol . 1981; 12 1060-1084
71 Fujita M, Furukawa H, Hattori M. et al . Sequential observation of liver cell regeneration after massive hepatic necrosis in auxiliary partial orthotopic liver transplantation. Mod Pathol . 2000; 13 152-157
72 Medvinsky A, Smith A. Stem cells: Fusion brings down barriers. Nature . 2003; 422 823-825
73 Su Q, Liu Y F, Zhang J F. et al . Expression of insulin-like growth factor II in hepatitis B, cirrhosis and hepatocellular carcinoma: its relationship with hepatitis B virus antigen expression. Hepatology . 1994; 20 788-799
74 Cassell H S, Price P, Olver S D, Yeoh G C. The association between murine cytomegalovirus induced hepatitis and the accumulation of oval cells. Int J Exp Pathol . 1998; 79 433-441
75 Ihrig M, Schrenzel M D, Fox J G. Differential susceptibility to hepatic inflammation and proliferation in AXB recombinant inbred mice chronically infected with Helicobacter hepaticus. Am J Pathol . 1999; 155 571-582
76 Crosby H, Hubscher S, Fabris L. et al . Immunolocalization of putative human liver progenitor cells in livers from patients with end-stage primary biliary cirrhosis and sclerosing cholangitis using the monoclonal antibody OV-6. Am J Pathol . 1998; 152 771-779
77 Saxena R, Hytiroglou P, Thung S N, Theise N D. Destruction of canals of Hering in primary biliary cirrhosis. Hum Pathol . 2002; 33 983-988
78 Slott P A, Liu M H, Tavoloni N. Origin, pattern, and mechanism of bile duct proliferation following biliary obstruction in the rat. Gastroenterology . 1990; 99 466-477
79 Van Eyken P, Sciot R, Desmet V J. A cytokeratin immunohistochemical study of cholestatic liver disease: evidence that hepatocytes can express “bile duct-type” cytokeratins. Histopathology . 1989; 15 125-135
80 Desmet V J. Modulation of biliary epithelium. In: Reutter W, Popper H, Arias IM, et al, eds. Modulation of Liver Cell Expression Lancaster, England: M.T.P. Press Limited 1987: 195-214
81 Ohlson L C, Koroxenidou L, Hallstrom I P. Inhibition of in vivo rat liver regeneration by 2-acetylaminofluorene affects the regulation of cell cycle-related proteins. Hepatology . 1998; 27 691-696
82 Lindeman B, Skarpen E, Oksvold M P, Huitfeldt H S. The carcinogen 2-acetylaminofluorene inhibits activation and nuclear accumulation of cyclin-dependent kinase 2 in growth- induced rat liver. Mol Carcinog . 2000; 27 190-199
83 Mehta K, Van Thiel H D, Shah N, Mobarhan S. Nonalcoholic fatty liver disease: pathogenesis and the role of antioxidants. Nutr Rev . 2002; 60 289-293
84 Tsukamoto H, Lu S C. Current concepts in the pathogenesis of alcoholic liver injury. FASEB J . 2001; 15 1335-1349
85 Crary G S, Albrecht J H. Expression of cyclin-dependent kinase inhibitor p21 in human liver. Hepatology . 1998; 28 738-743
86 Wands J R, Carter E A, Bucher N L, Isselbacher K J. Inhibition of hepatic regeneration in rats by acute and chronic ethanol intoxication. Gastroenterology . 1979; 77 528-531
87 Selzner M, Clavien P A. Failure of regeneration of the steatotic rat liver: disruption at two different levels in the regeneration pathway. Hepatology . 2000; 31 35-42
88 Yang S Q, Lin H Z, Mandal A K, Huang J, Diehl A M. Disrupted signaling and inhibited regeneration in obese mice with fatty livers: implications for nonalcoholic fatty liver disease pathophysiology. Hepatology . 2001; 34 694-706
89 Roskams T, van Eyken P, Desmet V. Human liver growth and development. In: Strain AJ, Diehl AM, eds. Liver Growth and Repair London: Chapman and Hall 1998: 541-557
90 Van Eyken P, Desmet V J. Development of intrahepatic bile ducts, ductular metaplasia of hepatocytes, and cytokeratin patterns in various types of human hepatic neoplasms. In: Sirica AE, ed. The Role of Cell Types in Hepatocarcinogenesis Boca Raton: CRC Press 1992: 227-263
91 Stosiek P, Kasper M, Karsten U. Expression of cytokeratin 19 during human liver organogenesis. Liver . 1990; 10 59-63
92 Van Eyken P, Sciot R, Callea F. et al . The development of the intrahepatic bile ducts in man: a keratin-immunohistochemical study. Hepatology . 1988; 8 1586-1595
93 Libbrecht L, Cassiman D, Desmet V, Roskams T. The correlation between portal myofibroblasts and development of intrahepatic bile ducts and arterial branches in human liver. Liver . 2002; 22 252-258
94 Fausto N, Lemire J M, Shiojiri N. Oval cells in liver carcinogenesis: Cell lineages in hepatic development and the identification of facultative stem cells in normal liver. In: Sirica AE, ed. The Role of Cell Types in Hepatocarcinogenesis Boca Raton: CRC Press 1992: 89-109
95 Van Eyken P, Desmet V J. Development of Intrahepatic Bile Ducts, Ductular Metaplasia of Hepatocytes, and Cytokeratin Patterns in Various Types of Human Hepatic Neoplasms. Boca Raton: CRC Press; 1992
96 Roskams T, Desmet V J. Parathyroid hormone-related peptide and development of intrahepatic bile ducts in man. Int Hepatol Comm . 1994; 2 121-127
97 Shah K D, Gerber M A. Development of intrahepatic bile ducts in humans. Possible role of laminin. Arch Pathol Lab Med . 1990; 114 597-600
98 Roskams T, Campos R V, Drucker D J, Desmet V J. Reactive human bile ductules express parathyroid hormone-related peptide. Histopathology . 1993; 23 11-19
99 Roskams T, van den Oord J J, De Vos R, Desmet V J. Neuroendocrine features of reactive bile ductules in cholestatic liver disease. Am J Pathol . 1990; 137 1019-1025
100 Crosby H, Hubscher S, Joplin R, Kelly D, Strain A. Immunolocalization of OV-6, a putative progenitor cell marker in human fetal and diseased pediatric liver. Hepatology . 1998; 28 980-985
101 Baumann U, Crosby H A, Ramani P, Kelly D A, Strain A J. Expression of the stem cell factor receptor c-kit in normal and diseased pediatric liver: identification of a human hepatic progenitor cell?. Hepatology . 1999; 30 112-117
102 Crosby H A, Hubscher S G, Joplin R E, Kelly D A, Strain A J. Immunolocalization of OV-6, a putative progenitor cell marker in human fetal and diseased pediatric liver. Hepatology . 1998; 28 980-985
103 Ruck P, Xiao J-C, Kaiserling E. Small epithelial cells and the histogenesis of hepatoblastoma. Electron microscopic, immunoelectron microscopic, and immunohistochemical findings. Am J Pathol . 1996; 148 321-329
104 Ruck P, Xiao J-C, Pietch T, Schweinitz V, Kaiserling E. Hepatic stem-like cells in hepatoblastoma: expression of cytokeratin 7, albumin and oval cell associated antigens detected by OV-1 and OV-6. Histopathology . 1997; 31 324-329
105 Zimmermann A. Hepatoblastoma with cholangioblastic features (`cholangioblastic hepatoblastoma') and other liver tumors with bimodal differentiation in young patients. Med Pediatr Oncol . 2002; 39 487-491
106 Wiemann S U, Satyanarayana A, Tsahuridu M. et al . Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. FASEB J . 2002; 16 935-942
107 Murphy F, Iredale J. The telomere hypothesis for progressive liver cirrhosis. J Hepatol . 2003; 38 378-379
108 Bisgaard H C, Holmskov U, Santoni-Rugiu E. et al . Heterogeneity of ductular reactions in adult rat and human liver revealed by novel expression of deleted in malignant brain tumor 1. Am J Pathol . 2002; 161 1187-1198
109 Desmet V. Organizational principles. In: Arias I, Boyer JL, Chisari F, et al, eds. The Liver Biology and Pathobiology, 4th ed. Philadelphia: Lippincott Williams and Wilkins; 2001: 3-15
110 Cassiman D, Denef C, Desmet V J, Roskams T. Human and rat hepatic stellate cells express neurotrophins and neurotrophin receptors. Hepatology . 2001; 33 148-158
111 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
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
113 Desmet V, Roskams T, Van Eyken P. Ductular reaction in the liver. Pathol Res Pract . 1995; 191 513-524
114 Ramadori G, Neubauer K, Odenthal M. et al . The gene of hepatocyte growth factor is expressed in fat-storing cells of rat liver and is downregulated during cell growth and by transforming growth factor-beta. Biochem Biophys Res Commun . 1992; 183 739-742
115 Niki T, Pekny M, Hellemans K. et al . Class VI intermediate filament protein Nestin is induced during activation of rat hepatic stellate cells. Hepatology . 1999; 29 520-527
116 Cassiman D, van Pelt J, De Vos R. et al . Synaptophysin, a novel marker for human and rat hepatic stellate cells. Am J Pathol . 1999; 155 1831-1839
117 Cassiman D, Libbrecht L, Sinelli N. et al . The vagal nerve stimulates activation of the hepatic progenitor cell compartment via muscarinic acetylcholine receptor type 3. Am J Pathol . 2002; 161 521-530
118 Burr A W, Carpenter M R, Hines J E, Gullick W J, Burt A D. Intrahepatic distribution of transforming growth factor-alpha (TGF alpha) during liver regeneration following carbon tetrachloride-induced necrosis. J Pathol . 1993; 170 95-100
119 Evarts R P, Nakatsukasa H, Marsden E R, Hu Z, Thorgeirsson S S. Expression of transforming growth factor-alpha in regenerating liver and during hepatic differentiation. Mol Carcinog . 1992; 5 25-31
120 Hu Z, Evarts R P, Fujio K, Marsden E R, Thorgeirsson S S. Expression of hepatocyte growth factor and c-met genes during hepatic differentiation and liver development in the rat. Am J Pathol . 1993; 142 1823-1830
121 Bisgaard H C, Santoni-Rugiu E, Nagy P, Thorgeirsson S S. Modulation of the plasminogen activator/plasmin system in rat liver regenerating by recruitment of oval cells. Lab Invest . 1998; 78 237-246
122 Kaplanski C, Pauley C J, Griffiths T G, Kawabata T T, Ledwith B J. Differentiation of rat oval cells after activation of peroxisome proliferator-activated receptor alpha43. Cancer Res . 2000; 60 580-587
123 Kiss A, Schnur J, Szabo Z, Nagy P. Immunohistochemical analysis of atypical ductular reaction in the human liver, with special emphasis on the presence of growth factors and their receptors. Liver . 2001; 21 237-246
124 Fausto N, Mead J E. Regulation of liver growth: protooncogenes and transforming growth factors. Lab Invest . 1989; 60 4-13
125 Fausto N, Mead J E, Gruppuso P A, Braun L. TGF-beta in liver development, regeneration and carcinogenesis. Ann N Y Acad Sci . 1990; 593 231-242
126 Hsia C C, Thorgeirsson S S, Tabor E. Expression of hepatitis B surface and core antigens and transforming growth factor-alpha in “oval cells” of the liver in patients with hepatocellular carcinoma. J Med Virol . 1994; 43 216-221
127 Joplin R, Hishida T, Tsubouchi H. et al . Human intrahepatic biliary epithelial cells proliferate in vitro in response to human hepatocyte growth factor. J Clin Invest . 1992; 90 1284-1289
128 Roskams T, Moshage H, Depla E. et al . Parathyroid hormone-related peptide is expressed and rapidly inducible in human liver cell cultures that have a bile duct phenotype. J Hepatol . 1995; 23 160-165
129 Roskams T, Desmet V. Parathyroid-hormone-related peptides: a new class of multifunctional proteins. Am J Pathol . 1997; 150 779-785
130 Roskams T, De Vos R, David G, Van Damme B, Desmet V. Heparan sulphate proteoglycan expression in human primary liver tumours. J Pathol . 1998; 185 290-297
131 Roskams T, De Vos R, Rosenbaum J, David G, Desmet V. Integral membrane and matrix heparan sulfate proteoglycan expression in chronic cholestatic human liver diseases. Hepatology . 1996; 24 524-532
132 Roskams T, Moshage H, De Vos R. et al . Heparan sulfate proteoglycan expression in normal human liver. Hepatology . 1995; 21 950-958
133 Raines E W, Ross R. Compartmentalization of PDGF on extracellular binding sites dependent on exon-6-encoded sequences. J Cell Biol . 1992; 116 533-543
134 Kelly J L, Sanchez A, Brown G S, Chesterman C N, Sleigh M J. Accumulation of PDGF B and cell-binding forms of PDGF A in the extracellular matrix. J Cell Biol . 1993; 121 1153-1163
135 Masumoto A, Yamamoto N. Stimulation of DNA synthesis in hepatocytes by hepatocyte growth factor bound to extracellular matrix. Biochem Biophys Res Commun . 1993; 191 1218-1223
136 Flaumenhaft R, Rifkin D B. The extracellular regulation of growth factor action. Mol Biol Cell . 1992; 3 1057-1065
137 Ros J, Libbrecht L, Geuken M, Jansen P, Roskams T. High expression of MDR1, MRP1 and MRP3 in the hepatic progenitor cell compartment and hepatocytes in severe human liver disease (in press). J Pathol .
138 Jansen P L, Roskams T. Why are patients with liver disease jaundiced? ATP-binding cassette transporter expression in human liver disease. J Hepatol . 2001; 35 811-813
139 Thorgeirsson S S. Target cell populations in virus-associated hepatocarcinogenesis. Princess Takamatsu Symp . 1995; 25 163-170
140 Imoto M, Nishimura D, Fukuda Y. et al . Immunohistochemical detection of alpha-fetoprotein, carcinoembryonic antigen, and ferritin in formalin-paraffin sections from hepatocellular carcinoma. Am J Gastroenterol . 1985; 80 902-906
141 Van Eyken P, Sciot R, Paterson A. et al . Cytokeratin expression in hepatocellular carcinoma: an immunohistochemical study. Hum Pathol . 1988; 12 562-568
142 Wu P C, Lai V C, Fang J W. et al . Hepatocellular carcinoma expressing both hepatocellular and biliary markers also expresses cytokeratin 14, a marker of bipotential progenitor cells. J Hepatol . 1999; 31 965-966
143 Crosby H A, Kelly D A, Strain A J. Human hepatic stem-like cells isolated using c-kit or CD34 can differentiate into biliary epithelium. Gastroenterology . 2001; 120 534-544
144 Fabris L, Strazzabosco M, Crosby H A. et al . Characterization and isolation of ductular cells coexpressing neural cell adhesion molecule and Bcl-2 from primary cholangiopathies and ductal plate malformations. Am J Pathol . 2000; 156 1599-1612