Progenitor cell involvement in cirrhotic human liver diseases: from controversy to consensus
2003; Elsevier BV; Volume: 39; Issue: 3 Linguagem: Inglês
10.1016/s0168-8278(03)00333-7
ISSN1600-0641
Autores Tópico(s)Liver Disease and Transplantation
ResumoSupport for the liver progenitor cell hypothesis has come mainly from rodent models of chemical hepatocarcinogenesis [1Opie E.L. The pathogenesis of tumors of the liver produced by butter yellow.J Exp Med. 1944; 80: 231-246Crossref PubMed Scopus (102) Google Scholar, 2Farber 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: 142-148PubMed Google Scholar, 3Grisham J.W. Hartroft W.S. Morphologic identification by electronmicroscopy of oval cells in experimental hepatic degeneration.Lab Invest. 1961; 10: 317-332PubMed Google Scholar, 4Fausto N. Hepatocyte differentiation and liver progenitor cells.Curr Opin Cell Biol. 1990; 2: 1036-1042Crossref PubMed Scopus (115) Google Scholar, 5Sell S. Is there a liver stem cell?.Cancer Res. 1990; 50: 3811-3815PubMed Google Scholar], from liver cell regeneration after chemical injury [6Wilson J.W. Leduc E.H. Role of cholangioles in restoration of the liver of the mouse after dietary injury.J Pathol Bacteriol. 1958; 76: 441-449Crossref PubMed Scopus (143) Google Scholar, 7Lemire 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: 535-552PubMed Google Scholar, 8Thorgeirsson S.S. Hepatic stem cells in liver regeneration.FASEB J. 1996; 10: 1249-1256Crossref PubMed Scopus (295) Google Scholar] and from cell culture data (for review see ref. [[9]Fausto N. Liver stem cells.in: Arias I.M. Boyer J.L. Fausto N. Jacoby W.B. Schachter D.A. Shafritz D.A. The liver: biology and pathobiology. 3rd ed. Raven Press, New York1994: 1501-1518Google Scholar]). In these models, a periportal population of small ‘primitive’ epithelial cells proliferates in association with or before hepatocyte multiplication. These cells were called oval cells because of their shape [1Opie E.L. The pathogenesis of tumors of the liver produced by butter yellow.J Exp Med. 1944; 80: 231-246Crossref PubMed Scopus (102) Google Scholar, 2Farber 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: 142-148PubMed Google Scholar]. Oval cells are related to terminal biliary ductules and the so-called canals of Hering [7Lemire 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: 535-552PubMed Google Scholar, 10Grisham J.W. Cell types in long-term propagable cultures of rat liver.Ann N Y Acad Sci. 1980; 349: 128-137Crossref PubMed Scopus (145) Google Scholar, 11Germain L. Noel M. Gourdeau H. Marceau N. Promotion of growth and differentiation of rat ductular oval cells in primary culture.Cancer Res. 1988; 48: 368-378PubMed Google Scholar, 12Lenzi R. Liu M.H. Tarsetti F. Slott P.A. Alpini G. Zhai W.R. 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: 390-402PubMed Google Scholar, 13Paku 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: 1313-1323Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar] and they express phenotypic markers of both (immature) hepatocytes (like alpha-fetoprotein and albumin) and bile duct cells (like bile duct type cytokeratins) [14Germain 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: 673-681PubMed Google Scholar, 15Hixson 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: 3750-3760PubMed Google Scholar, 16Dunsford 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: 4894-4900PubMed Google Scholar, 17Dabeva M.D. Alpini G. Hurston E. Shafritz D.A. Models for hepatic progenitor cell activation.Proc Soc Exp Biol Med. 1993; 204: 242-252Crossref PubMed Scopus (60) Google Scholar]. They constitute a heterogeneous cell population [14Germain 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: 673-681PubMed Google Scholar, 15Hixson 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: 3750-3760PubMed Google Scholar, 17Dabeva M.D. Alpini G. Hurston E. Shafritz D.A. Models for hepatic progenitor cell activation.Proc Soc Exp Biol Med. 1993; 204: 242-252Crossref PubMed Scopus (60) Google Scholar, 18Dunsford 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: 4887-4893PubMed Google Scholar, 19Dabeva 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: 1606-1620PubMed Google Scholar, 20Mandache 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: 59-73Crossref PubMed Scopus (9) Google Scholar], but at least a subset of oval cells is pluripotent and has the capacity to differentiate towards hepatocytes, bile ductular cells and intestinal epithelium and can give rise to hepatocellular carcinoma and cholangiocellular carcinoma [5Sell S. Is there a liver stem cell?.Cancer Res. 1990; 50: 3811-3815PubMed Google Scholar, 10Grisham J.W. Cell types in long-term propagable cultures of rat liver.Ann N Y Acad Sci. 1980; 349: 128-137Crossref PubMed Scopus (145) Google Scholar, 21Desmet V. Experimentele levercarcinogenese. Histochemische studie. Arscia, Brussels1963Google Scholar, 22Evarts 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: 1737-1740Crossref PubMed Scopus (413) Google Scholar, 23Tatematsu 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: 354-362PubMed Google Scholar, 24Tsao M.S. Grisham J.W. Hepatocarcinomas, cholangiocarcinomas, and hepatoblastomas produced by chemically transformed cultured rat liver epithelial cells.Am J Pathol. 1987; 127: 168-181PubMed Google Scholar, 25Evarts R.P. Hu Z. Omori N. Omori M. Marsden E.R. Thorgeirsson S.S. Precursor-product relationship between oval cells and hepatocytes: comparison between tritiated thymidine and bromodeoxyuridine as tracers.Carcinogenesis. 1996; 17: 2143-2151Crossref PubMed Scopus (67) Google Scholar, 26Yasui O. Miura N. Terada K. Kawarada Y. Koyama K. Sugiyama T. Isolation of oval cells from Long-Evans Cinnamon rats and their transformation into hepatocytes in vivo in the rat liver.Hepatology. 1997; 25: 329-334PubMed Google Scholar, 27Alison M.R. Poulsom R. Forbes S.J. Update on hepatic stem cells.Liver. 2001; 21: 367-373Crossref PubMed Scopus (82) Google Scholar]. Although controversial for a long time, it becomes now generally accepted that also in human liver, progenitor cells exist and are activated in different liver diseases [28Libbrecht L. Roskams T. Hepatic progenitor cells in human liver diseases.Semin Cell Dev Biol. 2002; 13: 389-396Crossref PubMed Scopus (177) Google Scholar, 29Sell S. Comparison of liver progenitor cells in human atypical ductular reactions with those seen in experimental models of liver injury.Hepatology. 1998; 27: 317-331Crossref PubMed Scopus (127) Google Scholar, 30Roskams T. De Vos R. Van Eyken P. Miyazaki H. Van Damme B. Desmet V. Hepatic OV-6 expression in human liver disease and rat experiments: evidence for hepatic progenitor cells in man.J Hepatol. 1998; 29: 455-463Abstract Full Text PDF PubMed Scopus (266) Google Scholar, 31Theise N.D. Saxena R. Portmann B.C. Thung S.N. Yee H. Chiriboga L. et al.The canals of Hering and hepatic stem cells in humans.Hepatology. 1999; 30: 1425-1433Crossref PubMed Scopus (638) Google Scholar, 32Haque S. Haruna Y. Saito K. Nalesnik M.A. Atillasoy E. Thung S.N. et al.Identification of bipotential progenitor cells in human liver regeneration.Lab Invest. 1996; 75: 699-705PubMed Google Scholar]. Human liver progenitor cells have mainly been studied in regeneration after severe hepatocellular necrosis [30Roskams T. De Vos R. Van Eyken P. Miyazaki H. Van Damme B. Desmet V. Hepatic OV-6 expression in human liver disease and rat experiments: evidence for hepatic progenitor cells in man.J Hepatol. 1998; 29: 455-463Abstract Full Text PDF PubMed Scopus (266) Google Scholar, 32Haque S. Haruna Y. Saito K. Nalesnik M.A. Atillasoy E. Thung S.N. et al.Identification of bipotential progenitor cells in human liver regeneration.Lab Invest. 1996; 75: 699-705PubMed Google Scholar, 33Roskams T. De Vos R. van den Oord J.J. Desmet V. Cells with neuroendocrine features in regenerating human liver.APMIS Suppl. 1991; 23: 32-39PubMed Google Scholar, 34Gerber 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: 70-74PubMed Google Scholar, 35Lowes 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: 537-541Abstract Full Text Full Text PDF PubMed Scopus (405) Google Scholar, 36Fujita M. Furukawa H. Hattori M. Todo S. Ishida Y. Nagashima K. Sequential observation of liver cell regeneration after massive hepatic necrosis in auxiliary partial orthotopic liver transplantation.Mod Pathol. 2000; 13: 152-157Crossref PubMed Google Scholar], but recent studies show that this cell compartment is also activated in chronic viral hepatitis [37Libbrecht 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: 373-378Crossref PubMed Scopus (177) Google Scholar, 38Sakamoto S. Yachi A. Anzai T. Wada T. AFP-producing cells in hepatitis and in liver cirrhosis.Ann N Y Acad Sci. 1975; 259: 253-258Crossref PubMed Scopus (37) Google Scholar, 39Xiao 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: 141-149Crossref PubMed Scopus (66) Google Scholar], alcoholic liver disease [40Ray M.B. Mendenhall C.L. French S.W. Gartside P.S. Bile duct changes in alcoholic liver disease.Liver. 1993; 13: 36-45Crossref PubMed Scopus (64) Google Scholar, 41Roskams T. Yang S. Koteish A. Durnez A. De Vos R. Huang X. et al.Oxidative stress and progenitor cell accumulation in mice and humans with alcoholic and non-alcoholic fatty liver disease.Am J Pathol. 2003; (in press)Google Scholar] and non-alcoholic fatty liver disease [[41]Roskams T. Yang S. Koteish A. Durnez A. De Vos R. Huang X. et al.Oxidative stress and progenitor cell accumulation in mice and humans with alcoholic and non-alcoholic fatty liver disease.Am J Pathol. 2003; (in press)Google Scholar], the most important carcinogenic conditions in the Western world. The study of Falkowski et al. [[42]Falkowski O. An H.J. Ianus I.A. Chiriboga L. Yee H. West A.B. Theise N.D. Regeneration of hepatocyte ‘buds’ in cirrhosis from intrabiliary stem cells.J Hepatol. 2003; 39: 357-364Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar] in this issue of the Journal describing the presence of ductular reaction-associated progenitor cells in different chronic liver diseases, further supports these studies. Activation of progenitor cells in chronic liver diseases implies that they form a potential target cell population for hepatocarcinogens [43Hsia 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: 1327-1333Crossref PubMed Scopus (179) Google Scholar, 44Libbrecht 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: 66-73Crossref PubMed Scopus (87) Google Scholar, 45Libbrecht L. De Vos R. Cassiman D. Desmet V. Aerts R. Roskams T. Hepatic progenitor cells in hepatocellular adenomas.Am J Surg Pathol. 2001; : 25Google Scholar, 46Libbrecht 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: 76-84Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar]. This could be an important drawback for possible future treatment of chronic liver diseases with progenitor cells, as these cells would be introduced in a carcinogenic microenvironment. Understanding the mechanisms of activation and differentiation of human hepatic progenitor cells in different liver diseases and the possible role of these cells in hepatocarcinogenesis [47Alison M. Golding M. Lalani el N. Sarraf C. Wound healing in the liver with particular reference to stem cells.Philos Trans R Soc Lond B Biol Sci. 1998; 353: 877-894Crossref PubMed Scopus (73) Google Scholar, 48Bustos M. Sangro B. Alzuguren P. Gil A.G. Ruiz J. Beraza N. et al.Liver damage using suicide genes. A model for oval cell activation.Am J Pathol. 2000; 157: 549-559Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar] is mandatory in order to fully assess the therapeutic potential of progenitor cells [[49]Sell S. The role of progenitor cells in repair of liver injury and in liver transplantation.Wound Repair Regen. 2001; 9: 467-482Crossref PubMed Scopus (57) Google Scholar]. Activation of hepatic progenitor cells (oval cells in rodents) is a term which is used for an increase in the number of progenitor cells and their differentiation towards the hepatocytic and/or biliary lineage [17Dabeva M.D. Alpini G. Hurston E. Shafritz D.A. Models for hepatic progenitor cell activation.Proc Soc Exp Biol Med. 1993; 204: 242-252Crossref PubMed Scopus (60) Google Scholar, 50Alison M. Sarraf C. Hepatic stem cells.J Hepatol. 1998; 29: 676-682Abstract Full Text PDF PubMed Scopus (111) Google Scholar, 51Alison M. Liver stem cells: a two compartment system.Curr Opin Cell Biol. 1998; 10: 710-715Crossref PubMed Scopus (95) Google Scholar]. In human liver, differentiation towards the biliary lineage leads to formation of reactive ductules, while differentiation towards the hepatocytic lineage occurs via intermediate hepatocytes. Reactive ductules are anastomosing strands of immature biliary cells with an oval nucleus and a small rim of cytoplasm, located at the mesenchymal (portal/septal)-parenchymal interface [30Roskams T. De Vos R. Van Eyken P. Miyazaki H. Van Damme B. Desmet V. Hepatic OV-6 expression in human liver disease and rat experiments: evidence for hepatic progenitor cells in man.J Hepatol. 1998; 29: 455-463Abstract Full Text PDF PubMed Scopus (266) Google Scholar, 31Theise N.D. Saxena R. Portmann B.C. Thung S.N. Yee H. Chiriboga L. et al.The canals of Hering and hepatic stem cells in humans.Hepatology. 1999; 30: 1425-1433Crossref PubMed Scopus (638) Google Scholar, 52Roskams T. De Vos R. Desmet V. ‘Undifferentiated progenitor cells’ in focal nodular hyperplasia of the liver.Histopathology. 1996; 28: 291-299Crossref PubMed Scopus (107) Google Scholar, 53Libbrecht 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: 233-239Crossref PubMed Scopus (58) Google Scholar, 54Roskams T. Desmet V. Ductular reaction and its diagnostic significance.Semin Diagn Pathol. 1998; 15: 259-269PubMed Google Scholar]. Intermediate hepatocytes are polygonal cells with a size and phenotype intermediate between progenitor cells and hepatocytes [30Roskams T. De Vos R. Van Eyken P. Miyazaki H. Van Damme B. Desmet V. Hepatic OV-6 expression in human liver disease and rat experiments: evidence for hepatic progenitor cells in man.J Hepatol. 1998; 29: 455-463Abstract Full Text PDF PubMed Scopus (266) Google Scholar, 31Theise N.D. Saxena R. Portmann B.C. Thung S.N. Yee H. Chiriboga L. et al.The canals of Hering and hepatic stem cells in humans.Hepatology. 1999; 30: 1425-1433Crossref PubMed Scopus (638) Google Scholar, 55Roskams T. De Vos R. van den Oord J.J. Desmet V. Cells with neuroendocrine features in regenerating human liver.APMIS Suppl. 1991; 23: 32-39PubMed Google Scholar, 56Demetris A. Seaberg E. Wennerberg A. Ionellie J. Michalopoulos G. Ductular reaction after submassive necrosis in humans. Special emphasis on analysis of ductular hepatocytes.Am J Pathol. 1996; 149: 439-448PubMed Google Scholar]. Different subtypes of progenitor cells have also been recognized by electron microscopy: the most immature progenitor cell type besides cells already featuring some biliary or hepatocytic features [20Mandache 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: 59-73Crossref PubMed Scopus (9) Google Scholar, 39Xiao 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: 141-149Crossref PubMed Scopus (66) Google Scholar, 57De 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: 1441-1450PubMed Google Scholar, 58Xiao 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: 454-460Crossref PubMed Scopus (41) Google Scholar]. This spectrum of cells ranging from the most immature phenotype to ductules and intermediate hepatocytes, forms a cell compartment with a specific phenotype, and is often referred to as the ‘progenitor cell compartment’. The term ‘ductular reaction’ refers to proliferation of pre-existing ductules, progenitor cell activation and intermediate hepatocytes [[54]Roskams T. Desmet V. Ductular reaction and its diagnostic significance.Semin Diagn Pathol. 1998; 15: 259-269PubMed Google Scholar]. From animal models we have learned that progenitor cells (oval cells) are activated when damage or loss of hepatocytes and/or cholangiocytes is combined with impaired regeneration of the mature cell types involved [[51]Alison M. Liver stem cells: a two compartment system.Curr Opin Cell Biol. 1998; 10: 710-715Crossref PubMed Scopus (95) Google Scholar]. Virtually every acute and chronic human liver disease is associated with damage to and loss of hepatocytes and/or cholangiocytes, the two major epithelial cell compartments of the liver. Injury can be caused by numerous triggers including viruses, alcohol, toxic substances, metabolic errors and unknown factors. Hence, it is not surprising that hepatic progenitor cell activation has been described in a variety of human liver diseases [[28]Libbrecht L. Roskams T. Hepatic progenitor cells in human liver diseases.Semin Cell Dev Biol. 2002; 13: 389-396Crossref PubMed Scopus (177) Google Scholar]. After submassive liver cell necrosis, reactive ductules, in continuity with intermediate hepatocytes, are seen at the periphery of the necrotic areas [31Theise N.D. Saxena R. Portmann B.C. Thung S.N. Yee H. Chiriboga L. et al.The canals of Hering and hepatic stem cells in humans.Hepatology. 1999; 30: 1425-1433Crossref PubMed Scopus (638) Google Scholar, 33Roskams T. De Vos R. van den Oord J.J. Desmet V. Cells with neuroendocrine features in regenerating human liver.APMIS Suppl. 1991; 23: 32-39PubMed Google Scholar, 56Demetris A. Seaberg E. Wennerberg A. Ionellie J. Michalopoulos G. Ductular reaction after submassive necrosis in humans. Special emphasis on analysis of ductular hepatocytes.Am J Pathol. 1996; 149: 439-448PubMed Google Scholar]. In patients studied with sequential liver biopsies, intermediate hepatocytes become more numerous with time and extend further into the liver lobule [30Roskams T. De Vos R. Van Eyken P. Miyazaki H. Van Damme B. Desmet V. Hepatic OV-6 expression in human liver disease and rat experiments: evidence for hepatic progenitor cells in man.J Hepatol. 1998; 29: 455-463Abstract Full Text PDF PubMed Scopus (266) Google Scholar, 59Fujita M. Furukawa H. Hattori M. Todo S. Ishida Y. Nagashima K. Sequential observation of liver cell regeneration after massive hepatic necrosis in auxiliary partial orthotopic liver transplantation.Mod Pathol. 2000; 13: 152-157Crossref PubMed Scopus (58) Google Scholar]. This sequence of changes suggests gradual differentiation of human putative progenitor cells into intermediate hepatocytes, in analogy with what is seen in rat models of chemical injury associated with impaired hepatocyte replication [13Paku 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: 1313-1323Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar, 29Sell S. Comparison of liver progenitor cells in human atypical ductular reactions with those seen in experimental models of liver injury.Hepatology. 1998; 27: 317-331Crossref PubMed Scopus (127) Google Scholar, 30Roskams T. De Vos R. Van Eyken P. Miyazaki H. Van Damme B. Desmet V. Hepatic OV-6 expression in human liver disease and rat experiments: evidence for hepatic progenitor cells in man.J Hepatol. 1998; 29: 455-463Abstract Full Text PDF PubMed Scopus (266) Google Scholar, 60Fausto N. Campbell J.S. The role of hepatocytes and oval cells in liver regeneration and repopulation.Mech Dev. 2003; 120: 117-130Crossref PubMed Scopus (572) Google Scholar]. In chronic cholestatic human liver diseases, progenitor cell activation has also been described, based on immunohistochemical and ultrastructural investigations [30Roskams T. De Vos R. Van Eyken P. Miyazaki H. Van Damme B. Desmet V. Hepatic OV-6 expression in human liver disease and rat experiments: evidence for hepatic progenitor cells in man.J Hepatol. 1998; 29: 455-463Abstract Full Text PDF PubMed Scopus (266) Google Scholar, 52Roskams T. De Vos R. Desmet V. ‘Undifferentiated progenitor cells’ in focal nodular hyperplasia of the liver.Histopathology. 1996; 28: 291-299Crossref PubMed Scopus (107) Google Scholar, 57De 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: 1441-1450PubMed Google Scholar, 61Crosby H. Hubscher S. Fabris L. Joplin R. Sell S. Kelly D. 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: 771-779PubMed Google Scholar, 62Saxena R. Hytiroglou P. Thung S.N. Theise N.D. Destruction of canals of Hering in primary biliary cirrhosis.Hum Pathol. 2002; 33: 983-988Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar]. On ultrastructure, cells intermediate between progenitor cells and bile duct cells are much more numerous than intermediate hepatocytes, suggesting that in biliary diseases, progenitor cells mainly differentiate towards the biliary lineage [30Roskams T. De Vos R. Van Eyken P. Miyazaki H. Van Damme B. Desmet V. Hepatic OV-6 expression in human liver disease and rat experiments: evidence for hepatic progenitor cells in man.J Hepatol. 1998; 29: 455-463Abstract Full Text PDF PubMed Scopus (266) Google Scholar, 53Libbrecht 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: 233-239Crossref PubMed Scopus (58) Google Scholar]. Intermediate hepatocytes are also present in the periportal zone in chronic cholestatic diseases, but less numerous than in regenerating liver after submassive necrosis [[30]Roskams T. De Vos R. Van Eyken P. Miyazaki H. Van Damme B. Desmet V. Hepatic OV-6 expression in human liver disease and rat experiments: evidence for hepatic progenitor cells in man.J Hepatol. 1998; 29: 455-463Abstract Full Text PDF PubMed Scopus (266) Google Scholar]. These cells form small periportal clusters and rosettes, seemingly in continuity with reactive ductules [30Roskams T. De Vos R. Van Eyken P. Miyazaki H. Van Damme B. Desmet V. Hepatic OV-6 expression in human liver disease and rat experiments: evidence for hepatic progenitor cells in man.J Hepatol. 1998; 29: 455-463Abstract Full Text PDF PubMed Scopus (266) Google Scholar, 52Roskams T. De Vos R. Desmet V. ‘Undifferentiated progenitor cells’ in focal nodular hyperplasia of the liver.Histopathology. 1996; 28: 291-299Crossref PubMed Scopus (107) Google Scholar, 54Roskams T. Desmet V. Ductular reaction and its diagnostic significance.Semin Diagn Pathol. 1998; 15: 259-269PubMed Google Scholar, 63Van 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: 125-135Crossref PubMed Scopus (133) Google Scholar]. This continuity is now proven by the three-dimensional reconstruction studies by Falkowski in this issue. The presence of intermediate hepatocytes can however still be interpreted in two ways. Either these intermediate cells are the result of differentiation of progenitor cells into hepatocytes, triggered by hepatocyte damage due to cholestasis. Another possibility, not yet ruled out is ‘metaplasia’ of hepatocytes towards a more biliary phenotype, as a protection mechanism against accumulation of toxic bile salts [[64]Desmet V.J. Modulation of biliary epithelium.in: Reutter W. Popper H. Arias I.M. Heinrich P.C. Keppler D. Landmann L. Modulation of liver cell expression. Lancaster, England, M.T.P. Press Limited. Kluwer Academic Publishers Group1987: 195-214Google Scholar]. Periportal hepatocytes are known to protect themselves against chronic cholestasis by upregulating bile salt transporters [[65]Ros J. Libbrecht L. Geuken M. Jansen P. Roskams T. High expression of MDR1, MRP1 and MRP3 in the hepatic progenitor cell comparment and hepatocytes in severe human liver disease.J Pathol. 2003; (in press)PubMed Google Scholar], pumping bile salts black into the blood. By doing this they become less cholestatic. Similarly, hepatocytes which undergo gradual change into a more biliary phenotype, will be able to survive, because this phenotype is more resistent to toxic bile salts. Falkowski et al. indeed show that intermediate hepatocytes, in continuity with reactive ductules/progenitor cells are rarely cholestatic; what is in fact expected and proofs that ductular metaplasia would be an effective protection mechanism. However, the authors interpret this absence of cholestasis as a proof against the existence of ductular metaplasia in chronic cholestatic diseases, which is an over interpretation of the data. They define cholestasis as bilirubinostasis and cholestatic Mallory bodies. These are severe signs of cholestasis, in fact signs of terminally damage … One would expect terminally damaged cholestatic hepatocytes to be isolated, not being able to link to the biliary tree, which is indeed what the authors of the article in this issue of J Hepatol show: isolated clusters of cholestatic hepatocytes are more numerous in cholestatic diseases than in chronic hepatitis. In addition, the authors use the high replicative rate of reactive ductules as an argument against the existence of ductular metaplasia of hepatoytes. However, they only studied a case of hepatitis C (in which reactive ductules are of course of the regenerative/proliferative type), and no cases of chronic cholestatic disease, the only situation in which the possibility of ductular metaplasia has ever been considered [63Van 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: 125-135Crossref PubMed Scopus (133) Google Scholar, 64Desmet V.J. Modulation of biliary epithelium.in: Reutter W. Popper H. Arias I.M. Heinrich P.C. Keppler D. Landmann L. Modulation of liver cell expression. Lancaster, England, M.T.P. Press Limited. Kluwer Academic Publishers Group1987: 195-214Google Scholar]. So overall, Falkowski et al. very nicely show continuity between reactive ductules and intermediate hepatocytes (not being severely cholestatic), and in addition they show that small cirrhotic nodules are often associated with ductules and intermediate hepatocytes. But, based on their data, they are not able to rule out ductular metaplasia of hepatocytes as part of the protection mechanisms of hepatocytes in chronic cholestatic diseases. In chronic viral hepatitis, progenitor cells are activated, even in mild degrees of inflammation [37Libbrecht 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: 373-378Crossref PubMed Scopus (177) Google Scholar, 39Xiao 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: 141-149Crossref PubMed Scopus (66) Google Scholar]. The number of progenitor cells (the degree of activation) correlates with the degree of inflammatory activity [37Libbrecht 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: 373-378Crossref PubMed Scopus (177) Google Scholar, 39Xiao 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: 141-149Crossref PubMed Scopus (66) Google Scholar]. Intermediate hepatocytes are only seen when a certain level of inflammation is reached, suggesting that progenitor cells only differentiate towards hepatocytes when a certain threshold of damage is reached [[37]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: 373-378Crossref PubMed Scopus (177) Google Scholar]. Similarly, in haemochromatosis, in alcoholic liver disease, in non-alcoholic fatty liver disease as well as in chronic biliary diseases, the degree of activation of progenitor cells and the number of intermediate hepatocytes correlate with the stage of the disease, which is a measure for the degree of damage [30Roskams T. De Vos R. Van Eyken P. Miyazaki H. Van Damme B. Desmet V. 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Failure of regeneration of the steatotic rat liver: disruption at two different levels in the regeneration pathway.Hepatology. 2000; 31: 35-42Crossref PubMed Scopus (223) Google Scholar]. Inhibition of replicative activity of mature hepatocytes is also shown in human liver diseases like alcoholic hepatitis and viral hepatitis [[71]Crary G.S. Albrecht J.H. Expression of cyclin-dependent kinase inhibitor p21 in human liver.Hepatology. 1998; 28: 738-743Crossref PubMed Scopus (66) Google Scholar]. Recently, Wiemann et al. illustrated that hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis induced by a wide variety of etiologies [[72]Wiemann S.U. Satyanarayana A. Tsahuridu M. Tillmann H.L. Zender L. Klempnauer J. et al.Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis.FASEB J. 2002; 16: 935-942Crossref PubMed Scopus (422) Google Scholar]. The study of Falkowski et al. in this issue very nicely confirms inhibition of hepatocyte replication in the cirrhotic stage of chronic viral hepatitis and that this is accompanied by an increased replication rate of the progenitor cell compartment. This increase in progenitor cell activation has also been shown in (cirhhotic) alcoholic and non-alcoholic fatty liver disease, conditions in which replication of hepatocytes is also inhibited [41Roskams T. Yang S. Koteish A. Durnez A. De Vos R. Huang X. et al.Oxidative stress and progenitor cell accumulation in mice and humans with alcoholic and non-alcoholic fatty liver disease.Am J Pathol. 2003; (in press)Google Scholar, 71Crary G.S. Albrecht J.H. Expression of cyclin-dependent kinase inhibitor p21 in human liver.Hepatology. 1998; 28: 738-743Crossref PubMed Scopus (66) Google Scholar]. Overall, oxidant-induced replicative senescence, as well as the progenitor cell response, seems to be stereotypical, irrespective of the type of underlying liver disease [30Roskams T. De Vos R. Van Eyken P. Miyazaki H. Van Damme B. Desmet V. Hepatic OV-6 expression in human liver disease and rat experiments: evidence for hepatic progenitor cells in man.J Hepatol. 1998; 29: 455-463Abstract Full Text PDF PubMed Scopus (266) Google Scholar, 35Lowes 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: 537-541Abstract Full Text Full Text PDF PubMed Scopus (405) Google Scholar, 37Libbrecht 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: 373-378Crossref PubMed Scopus (177) Google Scholar, 57De 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: 1441-1450PubMed Google Scholar]. Progenitor cell activation is particularly pronounced in the cirrhotic stage of a variety of chronic liver diseases, the stage in which most carcinomas arise. This should be kept in mind when progenitor cells are considered as a therapeutical option in chronic liver diseases.
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