RSS-Feed abonnieren
DOI: 10.1055/s-2004-815564
Progenitor Cells in Diseased Human Liver
Publikationsverlauf
Publikationsdatum:
14. Januar 2004 (online)
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
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