Characterization of the Differentiation Capacity of Rat-Derived Hepatic Stem Cells

ABSTRACT

The liver in an adult rat maintains a balance between cell gain and cell loss. Although normally proliferatively quiescent, hepatocyte loss such as that caused by partial hepatectomy (PH) invokes a rapid regenerative response to restore liver mass. This restoration of moderate cell loss and “wear and tear” renewal is largely achieved by hepatocyte self-replication. Furthermore, hepatocyte transplants in rats, in which a selective pressure for the transplanted cells can be applied, have shown that a certain proportion of hepatocytes can undergo significant clonal expansion, suggesting that hepatocytes themselves are the functional stem cells of the liver. Fetal liver may also harbor bipotential stem cells capable of sustained clonal expansion. More severe liver injury activates a potential stem cell compartment located within the canals of Hering, giving rise to cords of bipotential oval cells that can differentiate into hepatocytes and biliary epithelial cells. Other cell populations with hepatic potential reside in the bone marrow; whether these hematopoietic cells can function as stem cells for the rat liver remains to be confirmed. Pancreatic cells have also been found to have hepatocytic potential.

KEYWORDS

Stem cells - oval cells - side population cells - ABC membrane transporters - bone marrow - cholangiocytes - pancreatic cells

REFERENCES

• 1 Forbes S J, Vig P, Poulsom R. et al . Hepatic stem cells.  J Pathol . 2002;  197 510-518
• 2 Fausto N, Campbell J S. The role of hepatocytes and oval cells in liver regeneration and repopulation.  Mech Dev . 2003;  120 117-130
• 3 Alison M R, Poulsom R, Forbes S, Wright N A. An introduction to stem cells.  J Pathol . 2002;  197 419-423
• 4 Dabeva M D, Shafritz D A. The future of hepatic stem cells and liver repopulation.  Semin Liver Dis . 2003;  23
• 5 Fiegel H C, Kluth J, Lioznov M V. et al . Hepatic lineages isolated from developing rat liver show different ways of maturation.  Biochem Biophys Res Commun . 2003;  305 46-53
• 6 Fiegel H C, Park J J, Lioznov M V. et al . Characterization of cell types during rat liver development.  Hepatology . 2003;  37 148-154
• 7 Shafritz D A, Dabeva M D. Liver stem cells and model systems for liver repopulation.  J Hepatol . 2002;  36 552-564
• 8 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
• 9 Sandhu J S, Petkov P M, Dabeva M D, Shafritz D A. Stem cell properties and repopulation of the rat liver by fetal liver epithelial progenitor cells.  Am J Pathol . 2001;  159 1323-1334
• 10 Dabeva M D, Petkov P M, Sandhu J. et al . Proliferation and differentiation of fetal liver epithelial progenitor cells after transplantation into adult rat liver.  Am J Pathol . 2000;  156 2017-2031
• 11 Oertel M, Rosencrantz R, Chen Y Q. et al . Repopulation of rat liver by fetal hepatoblasts and adult hepatocytes transduced ex vivo with lentiviral vectors.  Hepatology . 2003;  37 994-1005
• 12 Petkov P M, Kim K, Sandhu J. et al . Identification of differentially expressed genes in epithelial stem/progenitor cells of fetal rat liver.  Genomics . 2000;  68 197-209
• 13 Laconi E, Oren R, Mukhopadhyay D K. et al . Long-term, near-total liver replacement by transplantation of isolated hepatocytes in rats treated with retrorsine.  Am J Pathol . 1998;  153 319-329
• 14 Oren R, Dabeva M D, Karnezis A N. et al . Role of thyroid hormone in stimulating liver repopulation in the rat by transplanted hepatocytes.  Hepatology . 1999;  30 903-913
• 15 Laconi S, Pillai S, Porcu P P. et al . Massive liver replacement by transplanted hepatocytes in the absence of exogenous growth stimuli in rats treated with retrorsine.  Am J Pathol . 2001;  158 771-777
• 16 Gordon G J, Coleman W B, Hixson D C, Grisham J W. Liver regeneration in rats with retrorsine-induced hepatocellular injury proceeds through a novel cellular response.  Am J Pathol . 2000;  156 607-619
• 17 Mugford C A, Kedderis G L. Sex-dependent metabolism of xenobiotics.  Drug Metab Rev . 1998;  30 441-498
• 18 Gordon G J, Butz G M, Grisham J W, Coleman W B. Isolation, short-term culture, and transplantation of small hepatocyte-like progenitor cells from retrorsine-exposed rats.  Transplantation . 2002;  73 1236-1243
• 19 Nagai H, Terada K, Watanabe G. et al . Differentiation of liver epithelial (stem-like) cells into hepatocytes induced by coculture with hepatic stellate cells.  Biochem Biophys Res Commun . 2002;  293 1420-1425
• 20 Couchie D, Holic N, Chobert M N. et al . In vitro differentiation of WB-F344 rat liver epithelial cells into the biliary lineage.  Differentiation . 2002;  69 209-215
• 21 Tateno C, Yoshizato K. Long-term cultivation of adult rat hepatocytes that undergo multiple cell divisions and express normal parenchymal phenotypes.  Am J Pathol . 1996;  148 383-392
• 22 Tada K, Roy-Chowdhury N, Prasad V. et al . Long-term amelioration of bilirubin glucuronidation defect in Gunn rats by transplanting genetically modified immortalized autologous hepatocytes.  Cell Transplant . 1998;  7 607-616
• 23 Guha C, Parashar B, Deb N J. et al . Normal hepatocytes correct serum bilirubin after repopulation of Gunn rat liver subjected to irradiation/partial resection.  Hepatology . 2002;  36 354-362
• 24 Gupta S. Hepatic polyploidy and liver growth control.  Semin Cancer Biol . 2000;  10 161-171
• 25 Semino C E, Merok J R, Crane G G. et al . Functional differentiation of hepatocyte-like spheroid structures from putative liver progenitor cells in three-dimensional peptide scaffolds.  Differentiation . 2003;  71 262-270
• 26 Guidotti J E, Bregerie O, Robert A. et al . Liver cell polyploidization: a pivotal role for binuclear hepatocytes.  J Biol Chem . 2003;  278 19095-19101
• 27 Nadal C, Zajdela F. Somatic polyploid cells in rat liver. I. The role of binuclear cells in the formation of the polyploid cells.  Exp Cell Res . 1966;  42 99-116
• 28 Sigal S H, Brill S, Fiorino A S, Reid L M. The liver as a stem cell and lineage system.  Am J Physiol . 1992;  263 G139-G148
• 29 Zajicek G, Oren R, Weinreb Jr M. The streaming liver.  Liver . 1985;  5 293-300
• 30 Bralet M P, Branchereau S, Brechot C, Ferry N. Cell lineage study in the liver using retroviral mediated gene transfer. Evidence against the streaming of hepatocytes in normal liver.  Am J Pathol . 1994;  144 896-905
• 31 Wright N A, Alison M R. The Biology of Epithelial Cell Populations, Vol 2.  Oxford: Clarendon Press; 1984
• 32 Sigal S H, Rajvanshi P, Gorla G R. et al . Partial hepatectomy-induced polyploidy attenuates hepatocyte replication and activates cell aging events.  Am J Physiol . 1999;  276 G1260-G1272
• 33 Weglarz T C, Degen J L, Sandgren E P. Hepatocyte transplantation into diseased mouse liver. Kinetics of parenchymal repopulation and identification of the proliferative capacity of tetraploid and octaploid hepatocytes.  Am J Pathol . 2000;  157 1963-1974
• 34 Alison M R, Golding M, Sarraf C E. et al . Liver damage in the rat induces hepatocyte stem cells from biliary epithelial cells.  Gastroenterology . 1996;  110 1182-1190
• 35 Alison M R, Golding M, Sarraf C E. Liver stem cells: when the going gets tough they get going.  Int J Exp Pathol . 1997;  78 365-381
• 36 Alison M R, Golding M, Lalani E-N, Sarraf C E. Wound healing in the liver with particular reference to stem cells.  Philos Trans R Soc Lond B Biol Sci . 1998;  353 1-18
• 37 Alison M, Golding M, Lalani E N. et al . Wholesale hepatocytic differentiation in the rat from ductular oval cells, the progeny of biliary stem cells.  J Hepatol . 1997;  26 343-352
• 38 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
• 39 Agelli M, Dello Sbarba P, Halay E D. et al . Putative liver progenitor cells: conditions for long-term survival in culture.  Histochem J . 1997;  29 205-217
• 40 Hixson D C, Chapman L, McBride A. et al . Antigenic phenotypes common to rat oval cells, primary hepatocellular carcinomas and developing bile ducts.  Carcinogenesis . 1997;  18 1169-1175
• 41 Hixson D C, Brown J, McBride A C, Affigne S. Differentiation status of rat ductal cells and ethionine-induced hepatic carcinomas defined with surface-reactive monoclonal antibodies.  Exp Mol Pathol . 2000;  68 152-169
• 42 Petersen B E, Goff J P, Greenberger J S, Michalopoulos G K. Hepatic oval cells express the hematopoietic stem cell marker Thy-1 in the rat.  Hepatology . 1998;  27 433-445
• 43 Baumann U, Crosby H A, Ramani P. et al . 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
• 44 Omori N, Omori M, Evarts R P. et al . Partial cloning of rat CD34 cDNA and expression during stem cell-dependent liver regeneration in the adult rat.  Hepatology . 1997;  26 720-727
• 45 Lemmer E R, Shepard E G, Blakolmer K. et al . Isolation from human fetal liver of cells co-expressing CD34 haematopoietic stem cell and CAM 5.2 pancytokeratin markers.  J Hepatol . 1998;  29 450-454
• 46 Petersen B E. Hepatic stem cells: coming full circle.  Blood Cells Mol Dis . 2001;  27 590-600
• 47 Hatch H M, Zheng D, Jorgensen M L, Petersen B E. SDF-1alpha/CXCR4: a mechanism for hepatic oval cell activation and bone marrow stem cell recruitment to the injured liver of rats.  Cloning Stem Cells . 2002;  4 339-351
• 48 Goodell M A, Brose K, Paradis G. et al . Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo.  J Exp Med . 1996;  183 1797-1806
• 49 Scharenberg C W, Harkey M A, Torok-Storb B. The ABCG2 transporter is an efficient Hoechst 33342 efflux pump and is preferentially expressed by immature human hematopoietic progenitors.  Blood . 2002;  99 507-512
• 50 Kim M, Turnquist H, Jackson J. et al . The multidrug resistance transporter ABCG2 (breast cancer resistance protein 1) effluxes Hoechst 33342 and is overexpressed in hematopoietic stem cells.  Clin Cancer Res . 2002;  8 22-28
• 51 Zhou S, Morris J J, Barnes Y. et al . Bcrp1 gene expression is required for normal numbers of side population stem cells in mice, and confers relative protection to mitoxantrone in hematopoietic cells in vivo.  Proc Natl Acad Sci USA . 2000;  99 12339-12344
• 52 Guo Y, Lubbert M, Engelhardt M. CD34(-) Hematopoietic stem cells: current concepts and controversies.  Stem Cells . 2003;  21 15-20
• 53 Ros J E, Libbrecht L, Geuken M. et al . High expression of MDR1, MRP1 and MRP3 in the hepatic progenitor cell compartment and hepatocytes in severe human liver disease (in press).  J Pathol. 2003; 
• 54 Shimano K, Satake M, Okaya A. et al . Hepatic oval cells have the side population phenotype defined by expression of ATP-binding cassette transporter ABCG2/BCRP1.  Am J Pathol . 2003;  163 3-9
• 55 Klein I, Sarkadi B, Varadi A. An inventory of the human ABC proteins.  Biochim Biophys Acta . 1999;  1461 237-262
• 56 Borst P, Elferink R O. Mammalian ABC transporters in health and disease.  Annu Rev Biochem . 2002;  71 537-592
• 57 Schinkel A H, Jonker J W. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview.  Adv Drug Deliv Rev . 2003;  55 3-29
• 58 Litman T, Brangi M, Hudson E. et al . The multidrug-resistant phenotype associated with overexpression of the new ABC half-transporter, MXR (ABCG2).  J Cell Sci . 2000;  113 2011-2021
• 59 Rocchi E, Khodjakov A, Volk E L. et al . The product of the ABC half-transporter gene ABCG2 (BCRP/MXP) is expressed in the plasma membrane.  Biochem Biophys Res Commun . 2000;  271 42-46
• 60 Small D M. Role of ABC transporters in secretion of cholesterol from liver into bile.  Proc Natl Acad Sci USA . 2003;  100 4-6
• 61 Scheffer G L, Kool M, de Haas M. et al . Tissue distribution and induction of human multidrug resistant protein 3.  Lab Invest . 2002;  82 193-201
• 62 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
• 63 Alison M R, Golding M H, Sarraf C E. Pluripotential liver stem cells: facultative stem cells located in the biliary tree.  Cell Prolif . 1996;  29 373-402
• 64 Yin L, Lynch D, Sell S. Participation of different cell types in the restitutive response of the rat liver to periportal injury induced by allyl alcohol.  J Hepatol . 1999;  31 497-507
• 65 Yin L, Sun M, Ilic Z. et al . Derivation, characterization, and phenotypic variation of hepatic progenitor cell lines isolated from adult rats.  Hepatology . 2002;  35 315-324
• 66 Shen C N, Slack J M, Tosh D. Molecular basis of transdifferentiation of pancreas to liver.  Nat Cell Biol . 2000;  2 879-887
• 67 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
• 68 Holic N, Suzuki T, Corlu A. et al . Differential expression of the rat gamma-glutamyl transpeptidase gene promoters along with differentiation of hepatoblasts into biliary or hepatocytic lineage.  Am J Pathol . 2000;  157 537-548
• 69 Kaplanski C, Pauley C J, Griffiths T G. et al . Differentiation of rat oval cells after activation of peroxisome proliferator-activated receptor alpha43.  Cancer Res . 2000;  60 580-587
• 70 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
• 71 Poulsom R, Alison M R, Forbes S J, Wright N A. Adult stem cell plasticity.  J Pathol . 2002;  197 441-456
• 72 Preston S L, Alison M R, Forbes S J. et al . The new stem cell biology: something for everyone.  Mol Pathol . 2003;  56 86-96
• 73 Forbes S J, Vig P, Poulsom R. et al . Adult stem cell plasticity: new pathways of tissue regeneration become visible.  Clin Sci (Lond) . 2002;  103 355-369
• 74 Grompe M. The role of bone marrow stem cells in liver regeneration.  Semin Liver Dis . 2003;  23
• 75 Alison M R, Poulsom R, Otto W R. et al . Plastic adult stem cells: will they graduate from the school of hard knocks?.  J Cell Sci . 2003;  116 599-603
• 76 Alison M R, Poulsom R, Otto W R. et al . Adult stem cell plasticity: the case gets stronger (in press).  J Clin Pathol . 2003; 
• 77 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
• 78 Avital I, Inderbitzin D, Aoki T. et al . Isolation, characterization, and transplantation of bone marrow-derived hepatocyte stem cells.  Biochem Biophys Res Commun . 2001;  288 156-164
• 79 Oh S H, Miyazaki M, Kouchi H. et al . Hepatocyte growth factor induces differentiation of adult rat bone marrow cells into a hepatocyte lineage in vitro.  Biochem Biophys Res Commun . 2000;  279 500-504
• 80 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
• 81 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
• 82 Ruhnke M, Ungefroren H, Zehle G. et al . Long-term culture and differentiation of rat embryonic stem cell-like cells into neuronal, glial, endothelial, and hepatic lineages.  Stem Cells . 2003;  21 428-436
• 83 Dabeva M D, Hwang S G, Vasa S R. et al . Differentiation of pancreatic epithelial progenitor cells into hepatocytes following transplantation into rat liver.  Proc Natl Acad Sci USA . 1997;  94 7356-7361
• 84 Zulewski H, Abraham E J, Gerlach M J. et al . Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes.  Diabetes . 2001;  50 521-533
• 85 Lechner A, Leech C A, Abraham E J. et al . Nestin-positive progenitor cells derived from adult human pancreatic islets of Langerhans contain side population (SP) cells defined by expression of the ABCG2 (BCRP1) ATP-binding cassette transporter.  Biochem Biophys Res Commun . 2002;  293 670-674
• 86 Marek C J, Cameron G A, Elrick L J. et al . Generation of hepatocytes expressing functional cytochromes P450 from a pancreatic progenitor cell line in vitro.  Biochem J . 2003;  370 763-769
• 87 Okumura K, Nakamura K, Hisatomi Y. et al . Salivary gland progenitor cells induced by duct ligation differentiate into hepatic and pancreatic lineages.  Hepatology . 2003;  38 104-113