Semin Liver Dis 2003; 23(4): 373-384
DOI: 10.1055/s-2004-815563
Copyright © 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Human Liver-Derived Stem Cells

Alastair J. Strain1,2 , Heather A. Crosby2 , Sarbjit Nijjar2 , Deirdre A. Kelly2 , Stefan G. Hubscher2
  • 1Professor of Biochemistry, University of Birmingham, Edgbaston, Birmingham, United Kingdom
  • 2Schools of Biosciences and Medicine, University of Birmingham, Edgbaston, Birmingham, United Kingdom
Further Information

Publication History

Publication Date:
14 January 2004 (online)

ABSTRACT

The search for human oval cells or bi-potential stem cells in the human liver is the subject of intensive investigation. Fetal hepatocytes (hepatoblasts) have some proliferative and bipotential capacity, but access to sufficient numbers of cells remains limiting. Candidate stem cells in the adult normal and diseased human liver have been identified using markers such as OV6, CD34, c-kit and NCAM. Lack of stem cell marker specificity however, remains a problem and further, more specific markers are required. The molecular signaling molecules and transcription factors that control proliferation and cell differentiation pathways into hepatocyte or biliary phenotype are beginning to emerge. However, whether any of the current liver stem cell approaches will be converted into effective clinical cell transplantation or gene therapy treatments has yet to be proven.

REFERENCES

  • 1 Higgins G M, Anderson R M. Experimental pathology of the liver. I. Restoration of the liver of the white rat following surgical removal.  Arch Pathol . 1931;  12 289-293
  • 2 Bucher N LR, Farmer S. Liver regeneration after partial hepatectomy: genes and metabolism. In: Strain AJ, Diehl AM, eds. Liver Growth and Repair London: Chapman & Hall 1998: 3-27
  • 3 Fausto N. Liver regeneration: from laboratory to clinic.  Liver Transpl . 2001;  7 835-844
  • 4 Farber E. Similarities in the sequence of early histological changes induced in the livers by ethionine, 2-acetylaminofluorene and 3-methyl-4-dimethylaminoazobenzene.  Cancer Res . 1956;  16 142-148
  • 5 Lenzi R, Liu M H, Tarsetti F. et al . Histogenesis of bile duct-like cells proliferating during ethionine carcinogenesis: evidence for a biliary epithelial nature of oval cells.  Lab Invest . 1992;  66 390-402
  • 6 Fausto N, Lemire J M, Shiojiri N. Cell lineages in hepatic development and the identification of progenitor cells in normal and injured liver.  Proc Soc Exp Biol Med . 1993;  204 237-241
  • 7 Sirica A E, Mathis G A, Sano N, Elmore L. Isolation, culture and transplantation of intra-hepatic biliary epithelial cells and oval cells.  Pathobiology . 1990;  58 44-64
  • 8 Thorgeirsson S S. Hepatic stem cells in liver regeneration.  FASEB J . 1996;  10 1249-1256
  • 9 Dabeva M A, 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
  • 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 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
  • 12 Zaret K. Regulatory phases of early liver development: paradigms of organogenesis.  Nat Rev Genet . 2002;  3 499-512
  • 13 Roskams T, Van Eyken P, Desmet V. Human liver growth and development. In: Strain AJ, Diehl AM, eds. Liver Growth and Repair London: Chapman & Hall 1998: 541-557
  • 14 Kubota H, Reid L M. Clonogenic hepatoblasts, common precursors for hepatocytic and biliary lineages, are lacking classical major histocompatibility complex class I antigen.  Proc Natl Acad Sci USA . 2000;  97 12132-12137
  • 15 Suzuki A, Zheng Y, Kondo R. et al . Flow cytometric separation and enrichment of hepatic progenitor cells in developing mouse liver.  Hepatology . 2000;  32 1230-1239
  • 16 Strain A J, Hill D J, Swenne I, Milner R DG. The regulation of DNA synthesis in human fetal hepatocytes by placental lactogen growth hormone and insulin-like growth factor I/somatomedin-C.  J Cell Physiol . 1987;  132 33-40
  • 17 Hoshi H, Kan M, McKeehan W L. Direct analysis of growth factor requirements for isolated human fetal hepatocytes.  In Vitro Cell Dev Biol . 1987;  23 723-732
  • 18 Kamiya A, Kinoshita T, Ito Y. et al . Fetal liver development requires a paracrine action of oncostatin M through the gp130 signal transducer.  EMBO J . 1999;  18 2127-2136
  • 19 Kamiya A, Kinoshita T, Miyajima A. Oncostatin M and hepatocyte growth factor induce hepatic maturation via distinct signaling pathways.  FEBS Lett . 2001;  492 90-94
  • 20 Mahli H, Irani A N, Gagandeep S, Gupta S. Isolation of human progenitor liver epithelial cells with extensive replication capacity and differentiation into mature hepatocytes.  J Cell Sci . 2002;  115 2679-2688
  • 21 Thung S N. The development of proliferating ductular structures in liver disease.  Arch Pathol Lab Med . 1990;  114 407-411
  • 22 De Vos R, Desmet V. Ultrastructural characteristics of novel epithelial cell types identified in human pathologic liver specimens with chronic ductular reaction.  Am J Pathol . 1992;  140 1441-1450
  • 23 Xiao J, Ruck P, Kaiserling E. Small epithelial cells in extra-hepatic biliary atresia: electron microscopic and immunoelectron microscopic findings suggest a close relationship to liver progenitor cells.  Histopathology . 1999;  35 454-460
  • 24 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
  • 25 Sell S. Heterogeneity and plasticity of hepatocyte lineages.  Hepatology . 2001;  33 738-750
  • 26 Nakanuma Y, Ohta G. Immunohistochemical study on bile ductular proliferation in various hepatobiliary diseases.  Liver . 1986;  6 205-211
  • 27 Sell S. Comparison of liver progenitor cells in human atypical ductular reactions with those seen in models of liver injury.  Hepatology . 1998;  27 317-332
  • 28 Vandersteenhoven A M, Burchette J, Michalopoulos G. Characterization of ductular hepatocytes in end-stage cirrhosis Arch Pathol Lab Med .  1990;  114 403-406
  • 29 Gerber M A, Thung S N, Shen S N, Stromeyer F W, Ishak K G. Phenotypic characterisation 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
  • 30 Roskams T A, Theise N D, Balabaud C. et al . Nomenclature of the finer branches of the biliary tree: canals, ductules and ductular reaction in human livers (in press). 
  • 31 Fabris L, Strazzabosco M, Crosby H A. et al . Characterization and isolation of ductular cells co-expressing neural cell adhesion molecule and Bcl-2 from primary cholangiopathies and ductal plate malformations.  Am J Pathol . 2000;  156 1599-1612
  • 32 Van Eyken P, Sciot R, Calea F, Desmet V J. A cytokeratin immunohistochemical study of focal nodular hyperplasia of the liver: further evidence that ductular metaplasia of hepatocytes contributes to ductular proliferation.  Liver . 1989;  9 372-377
  • 33 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
  • 34 Van den Heuvel C M, Slooff M J, Visser L. et al . Expression of anti-OV-6 antibody and anti NCAM antibody along the biliary line of normal and diseased human livers.  Hepatology . 2001;  33 1387-1393
  • 35 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
  • 36 Ruck P, Xiao J, Pietsch T. 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
  • 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 Crosby H A, Hubscher S, Fabris L. et al . Immunolocalization of putative human liver progenitor cells in liver of patients with end-stage primary biliary cirrhosis and sclerosing cholangitis using the monoclonal antibody OV-6.  Am J Pathol . 1998;  152 771-779
  • 39 Crosby H A, Hubscher S, Joplin R, Kelly D A, Strain A J. Immunolocalization of OV-6, a putative stem cell marker in human fetal and diseased liver.  Hepatology . 1998;  28 980-985
  • 40 Bisgaard H C, Parmelee D C, Dunsford H A, Sechi S, Thorgeirsson S S. Keratin 14 protein in cultured nonparenchymal rat hepatic epithelial cells: characterization of keratin 14 and keratin 19 as antigens for the commonly used mouse monoclonal antibody OV-6.  Mol Carcinog . 1993;  7 60-66
  • 41 Roskams T, van den Oord J J, De Vos R, Desmet V J. Neuroendocrine features of reactive bile ducts in cholestatic liver disease.  Am J Pathol . 1990;  137 1019-1025
  • 42 Roskams T, Campos R V, Drucker D J, Desmet V. Reactive human bile ducts express parathyroid hormone-related peptide.  Histopathology . 1993;  23 11-19
  • 43 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
  • 44 Fujio K, Evarts R P, Hu Z, Marsden E R, Thorgeirsson S S. Expression of stem cell factor and it's receptor, c-kit, during liver regeneration from putative stem cells in adult rat.  Lab Invest . 1994;  70 511-516
  • 45 Omori N, Omori M, Evarts R. et al . Partial cloning of rat CD34 cDNA and expression during stem cell-dependent liver regeneration in the rat.  Hepatology . 1997;  26 720-727
  • 46 Blakolmer K, Jaskiewicz K, Dunsford H A, Robson S C. Haemopoietic stem cell markers are expressed by ductal plate and bile duct cells in developing human liver.  Hepatology . 1995;  21 1510-1516
  • 47 Baumann U, Crosby H A, Ramani P, Kelly D A, Strain A J. Expression of stem cell factor receptor c-kit in normal and diseased paediatric liver.  Hepatology . 1999;  30 112-117
  • 48 Strain A J, Flynn D, Nijjar S S. et al .Recent developments in the biology of liver stem cells. In: Gupta S, Jansen PLM, Klempnauer J, Manns MP, eds. Hepatocyte Transplantation Falk Symposium 126. New York: Kluwer; 2002: 3-12
  • 49 Petersen B E, Bowen W C, Patrene K D. et al . Bone marrow as a potential source of hepatic oval cells.  Science . 1999;  284 1168-1170
  • 50 Theise N D, Badve S, Saxena R. et al . Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation.  Hepatology . 2000;  31 235-240
  • 51 Lagasse E, Connors H, Al-Dhalimy M. et al . Purified hematopoietic cells can differentiate into hepatocytes in vivo.  Nat Med . 2000;  6 1229-1234
  • 52 Mallet V, Mitchell C, Mezey E. et al . Bone marrow transplantation in mice leads to a minor population of hepatocytes that can be selectively amplified in vivo.  Hepatology . 2002;  35 799-804
  • 53 Avital I, Inderbitzin D, Aoki T. et al . Isolation, characterisation and transplantation of bone marrow derived hepatocyte stem cells.  Biochem Biophys Res Commun . 2001;  288 156-164
  • 54 Kakinuma S, Tanaka Y, Chinzei R. et al . Human umbilical cord blood as a source of transplantable hepatic progenitor cells.  Stem Cells . 2003;  21 217-227
  • 55 Danet G H, Luongo J L, Butler G. et al . C1qRp defines a new human stem cell population with hematopoietic and hepatic potential.  Proc Natl Acad Sci USA . 2002;  99 10441-10445
  • 56 Theise N D, Nimmakayalu M, Gardner R. et al . Liver from bone marrow in humans.  Hepatology . 2000;  32 11-16
  • 57 Alison M R, Poulsom R, Jeffery R. et al . Hepatocytes from non-hepatic adult stem cells.  Nature . 2000;  406 257
  • 58 Korbling M, Katz R, 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
  • 59 Newsome P, Johannessen I, Boyle S. et al . Human cord blood-derived cells can differentiate in the mouse liver with no evidence of cellular fusion.  Gastroenterology . 2003;  124 1891-1900
  • 60 Wang X, Montini E, Al-Dhalimy M, Lagasse E, Finegold M, Grompe M. Kinetics of liver repopulation after bone marrow transplantation.  Am J Pathol . 2002;  161 565-574
  • 61 Mitchell C, Fausto N. Bone marrow-derived hepatocytes: rare but promising.  Am J Pathol . 2002;  161 349-350
  • 62 Terada N, Hamazaki T, Oka M. et al . Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion.  Nature . 2002;  416 542-545
  • 63 Ying Q, Nichols J, Evans E P, Smith A G. Changing potency by spontaneous fusion.  Nature . 2002;  416 545-548
  • 64 Wang X, Willenbring H, Akkari Y. et al . Cell fusion is the principle source of bone-marrow-derived hepatocytes.  Nature . 2003;  422 897-901
  • 65 Vassilopoulos G, Wang P R, Russell D W. Transplanted bone marrow regenerates liver by cell fusion.  Nature . 2003;  422 901-904
  • 66 Yaswen P, Hayner N T, Fausto N. Isolation of oval cells by centrifugal elutriation and comparison with other cell types purified from normal and neoplastic liver.  Cancer Res . 1984;  44 324-331
  • 67 Coleman W, Grisham J. Epithelial-like stem cells of the rodent liver. In: Strain AJ, Diehl AM, eds. Liver Growth and Repair London: Chapman & Hall 1998: 50-99
  • 68 Rogler L E. Selective bipotential differentiation of mouse embryonic hepatoblasts in vitro.  Am J Pathol . 1997;  150 591-602
  • 69 Strick-Marchland H, Weiss M C. Inducible differentiation and morphogenesis of bi-potential liver cells from wild type mouse embryos.  Hepatology . 2002;  36 794-804
  • 70 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
  • 71 Choi K, Kennedy M, Kazarov A, Papadimitriou J C, Keller G. A common precursor for haematopoietic and endothelial cells.  Development . 1998;  125 725-732
  • 72 Crosby H A, Nijjar S S, Goyet J deV, Kelly D A, Strain A J. Progenitor cells of the biliary epithelial cell lineage.  Semin Cell Dev Biol . 2002;  13 397-403
  • 73 Murray L J, Young J C, Osborne L J. et al . Thrombopoietin, flt3, and kit ligands together suppress apoptosis of human mobilized CD34+ cells and recruit primitive CD34+ Thy1+ cells into rapid division.  Exp Hematol . 1999;  27 1019-1028
  • 74 Fiegel H C, Lioznov M V, Cortes-Dericks L. et al . Liver-specific gene expression in cultured human hematopoietic stem cells.  Stem Cells . 2003;  21 98-104
  • 75 Miyazaki M, Akiyama I, Sakaguchi M. et al . Improved conditions to induce hepatocytes from rat bone marrow cells in culture.  Biochem Biophys Res Commun . 2002;  298 24-30
  • 76 Okumoto K, Saito T, Hattori E. et al . Differentiation of bone marrow cells into cells that express liver-specific genes in vitro: implication of the Notch signals in differentiation.  Biochem Biophys Res Commun . 2003;  304 691-695
  • 77 Reyes M, Verfaillie C M. Characterisation of multipotent adult progenitor cells, a sub-population of mesenchymal stem cells.  Ann N Y Acad Sci . 2001;  938 231-235
  • 78 Schwartz R E, Reyes M, Koodie L. et al . Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells.  J Clin Invest . 2002;  109 1291-1302
  • 79 Artavanis-Tsakonas S, Rand M D, Lake R J. Notch signaling: cell fate control and signal integration in development.  Science . 1999;  284 770-776
  • 80 Karanu F N, Murdoch B, Gallacher L. et al . The notch ligand jagged-1 represents a novel growth factor of human haematopoietic stem cells.  J Exp Med . 2000;  192 1365-1372
  • 81 Krebs L T, Xue Y, Norton C R. et al . Notch signalling is essential for vascular morphogenesis in mice.  Genes Dev . 2000;  14 1343-1352
  • 82 Karanu F N, Murdoch B, Miyabayashi T. et al . Human homologues of Delta1 and Delta 4 function as itogenic regulators of primitive human haematopoietic cells.  Blood . 2001;  97 1960-1967
  • 83 Varnum-Finney B, Xu L, Brashem-Stein C. et al . Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive NotcH1 signaling.  Nat Med . 2000;  6 1278-1281
  • 84 Varnum-Finney B, Brasham-Stein C, Bernstein I D. Combined effects of Notch signaling and cytokines induce a multiple log increase in precursors with lymphoid and myeloid reconstituting ability.  Blood . 2003;  101 1784-1789
  • 85 Kunisato A, Chiba S, Nakagami-Yamaguchi E. et al . HES-1 preserves purified hematopoietic stem cells ex vivo and accumulates side population cells in vivo.  Blood . 2003;  101 1777-1783
  • 86 Lessard J, Sauvageau G. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells.  Nature . 2003;  423 255-260
  • 87 Park I K, Qian D, Kiel M. et al . Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells.  Nature . 2003;  423 302-305
  • 88 Nijjar S S, Crosby H A, Wallace L, Hubscher S G, Strain A J. Notch receptor expression in adult human liver: a possible role in normal bile duct formation and endothelial cell function.  Hepatology . 2001;  34 1184-1192
  • 89 Nijjar S S, Wallace L, Crosby H A, Hubscher S G, Strain A J. Altered notch ligand expression in human liver disease: further evidence for a role of the Notch signalling pathway in hepatic neovascularisation and biliary ductular defects.  Am J Pathol . 2002;  160 1695-1703
  • 90 Spinner N B, Colliton R P, Crosnier C. et al . Jagged 1 mutations in Alagille syndrome.  Hum Mutat . 2001;  17 18-33
  • 91 McCright B, Lozier J, Gridley T. A mouse model of Alagille syndrome: NotcH2 as a genetic modifier of Jag1 haploinsufficiency.  Development . 2002;  129 1075-1082
  • 92 Cereghini S. Liver enriched transcription factors.  FASEB J . 1996;  10 267-282
  • 93 Darlington G J. Molecular mechanisms of liver development and differentiation.  Curr Opin Cell Biol . 1999;  11 678-682
  • 94 Duncan S A. Mechanisms controling early development of the liver.  Mech Dev . 2003;  120 19-33
  • 95 Spath G F, Weiss M C. Hepatocyte nuclear factor 4 provokes expression of epithelial markers, acting as a morphogen in dedifferentiated hepatoma cells.  J Cell Biol . 1998;  140 935-946
  • 96 Bilir B M, Guinette D, Karrer F. et al . Hepatocyte transplantation in acute liver failure.  Liver Transpl . 2000;  6 32-40
  • 97 Fox I J, Chowdhury J R, Kaufman S S. et al . Treatment of the Crigler-Najjar syndrome type 1 with hepatocyte transplantation.  N Engl J Med . 1998;  338 1422-1426
  • 98 Li A P, Gorycki P D, HengstJG, et al. Present status of the application of cryopreserved hepatocytes in the evaluation of xenobiotics.  Chem Biol Interact . 1999;  121 117-123
  • 99 Strain A J, Neuberger J M. A bioartificial liver: state of the art.  Science . 2002;  295 1005-1009