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Global gene expression profiling reveals a key role of CD44 in hepatic oval-cell reaction after 2-AAF/CCl4 injury in rodents

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Abstract

Liver progenitors, so-called oval cells, proliferate remarkably from periportal areas after severe liver injury when hepatocyte regeneration is compromised. These cells invade far into the liver parenchyma. Molecular mechanisms underlying these behaviors of oval cells remain poorly understood. In this study, we treated rats with 2-acetylaminofluorene/carbon tetrachloride to induce hepatic oval cells. By expression microarray analysis, we investigated global gene expression profiles in liver tissue, with an emphasis on adhesion molecules, extracellular matrix proteins, matrix metalloproteinases (MMPs), growth factors/cytokines, and receptors that might contribute to the distinct behaviors of oval cells. Genes upregulated at least twofold were selected. We then performed immunostaining to verify the microarray results and identified expression of MMP-7 and CD44 in oval cells. Staining of cytokeratin (CK)-19, an oval-cell marker, was similar between oval cells located next to periportal areas and those located far within the parenchyma. In contrast, CD44 staining was more intense in the parenchyma than in periportal areas, suggesting a role of CD44 in oval-cell invasion. Moreover, newly differentiated CK-19+ hepatocytes within foci did not show CD44 staining, suggesting that CD44 is related to the undifferentiated oval-cell phenotype. We then investigated oval-cell reactivity in CD44-deficient mice fed an oval cell-inducing diet of 3,5-diethoxycarbonyl-1,4-dihydrocollidine. Results showed significantly reduced oval-cell reactivity in CD44-deficient mice. Thus, oval cells express MMP-7 and CD44, and CD44 appears to play critical roles in the proliferation, invasion, and differentiation of hepatic oval cells in rodents.

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References

  • Alison MR, Golding M, Sarraf CE, Edwards RJ, Lalani EN (1996) Liver damage in the rat induces hepatocyte stem cells from biliary epithelial cells. Gastroenterology 110:1182–1190

    Article  CAS  PubMed  Google Scholar 

  • Arai M, Yokosuka O, Fukai K, Imazeki F, Chiba T, Sumi H, Kato M, Takiguchi M, Saisho H, Muramatsu M, Seki N (2004) Gene expression profiles in liver regeneration with oval cell induction. Biochem Biophys Res Commun 317:370–376

    Article  CAS  PubMed  Google Scholar 

  • Asahina K, Sato H, Yamasaki C, Kataoka M, Shiokawa M, Katayama S, Tateno C, Yoshizato K (2002) Pleiotrophin/heparin-binding growth-associated molecule as a mitogen of rat hepatocytes and its role in regeneration and development of liver. Am J Pathol 160:2191–2205

    CAS  PubMed  Google Scholar 

  • Bisgaard HC, Muller S, Nagy P, Rasmussen LJ, Thorgeirsson SS (1999) Modulation of the gene network connected to interferon-gamma in liver regeneration from oval cells. Am J Pathol 155:1075–1085

    CAS  PubMed  Google Scholar 

  • Bisgaard HC, Holmskov U, Santoni-Rugiu E, Nagy P, Nielsen O, Ott P, Hage E, Dalhoff K, Rasmussen LJ, Tygstrup N (2002) Heterogeneity of ductular reactions in adult rat and human liver revealed by novel expression of deleted in malignant brain tumor 1. Am J Pathol 161:1187–1198

    CAS  PubMed  Google Scholar 

  • Braun L, Mead JE, Panzica M, Mikumo R, Bell GI, Fausto N (1988) Transforming growth factor beta mRNA increases during liver regeneration: a possible paracrine mechanism of growth regulation. Proc Natl Acad Sci USA 85:1539–1543

    Article  CAS  PubMed  Google Scholar 

  • Brooling JT, Campbell JS, Mitchell C, Yeoh GC, Fausto N (2005) Differential regulation of rodent hepatocyte and oval cell proliferation by interferon gamma. Hepatology 41:906–915

    Article  CAS  PubMed  Google Scholar 

  • Chiu CC, Huang GT, Chou SH, Chien CT, Chiou LL, Chang MH, Lee HS, Chen DS (2007) Characterization of cytokeratin 19-positive hepatocyte foci in the regenerating rat liver after 2-AAF/CCl(4) injury. Histochem Cell Biol 128:217–226

    Article  CAS  PubMed  Google Scholar 

  • Cho RW, Clarke MF (2008) Recent advances in cancer stem cells. Curr Opin Genet Dev 18:48–53

    Article  CAS  PubMed  Google Scholar 

  • Evarts RP, Nagy P, Marsden E, Thorgeirsson SS (1987) In situ hybridization studies on expression of albumin and alpha-fetoprotein during the early stage of neoplastic transformation in rat liver. Cancer Res 47:5469–5475

    CAS  PubMed  Google Scholar 

  • Evarts RP, Nagy P, Nakatsukasa H, Marsden E, Thorgeirsson SS (1989) In vivo differentiation of rat liver oval cells into hepatocytes. Cancer Res 49:1541–1547

    CAS  PubMed  Google Scholar 

  • Fausto N (2004) Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells. Hepatology 39:1477–1487

    Article  PubMed  Google Scholar 

  • Fausto N, Lemire JM, Shiojiri N (1993) Cell lineages in hepatic development and the identification of progenitor cells in normal and injured liver. Proc Soc Exp Biol Med 204:237–241

    CAS  PubMed  Google Scholar 

  • Fujio K, Evarts RP, Hu Z, Marsden ER, Thorgeirsson SS (1994) Expression of stem cell factor and its receptor, c-kit, during liver regeneration from putative stem cells in adult rat. Lab Invest 70:511–516

    CAS  PubMed  Google Scholar 

  • Fujio K, Hu Z, Evarts RP, Marsden ER, Niu CH, Thorgeirsson SS (1996) Coexpression of stem cell factor and c-kit in embryonic and adult liver. Exp Cell Res 224:243–250

    Article  CAS  PubMed  Google Scholar 

  • Hatch HM, Zheng D, Jorgensen ML, Petersen BE (2002) 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 4:339–351

    Article  CAS  PubMed  Google Scholar 

  • Hu Z, Evarts RP, Fujio K, Marsden ER, Thorgeirsson SS (1993) Expression of hepatocyte growth factor and c-met genes during hepatic differentiation and liver development in the rat. Am J Pathol 142:1823–1830

    CAS  PubMed  Google Scholar 

  • Hu Z, Evarts RP, Fujio K, Marsden ER, Thorgeirsson SS (1995) Expression of fibroblast growth factor receptors flg and bek during hepatic ontogenesis and regeneration in the rat. Cell Growth Differ 6:1019–1025

    CAS  PubMed  Google Scholar 

  • Jelnes P, Santoni-Rugiu E, Rasmussen M, Friis SL, Nielsen JH, Tygstrup N, Bisgaard HC (2007) Remarkable heterogeneity displayed by oval cells in rat and mouse models of stem cell-mediated liver regeneration. Hepatology 45:1462–1470

    Article  CAS  PubMed  Google Scholar 

  • Jensen CH, Jauho EI, Santoni-Rugiu E, Holmskov U, Teisner B, Tygstrup N, Bisgaard HC (2004) Transit-amplifying ductular (oval) cells and their hepatocytic progeny are characterized by a novel and distinctive expression of delta-like protein/preadipocyte factor 1/fetal antigen 1. Am J Pathol 164:1347–1359

    CAS  PubMed  Google Scholar 

  • Lee HS, Sherley JL, Chen JJ, Chiu CC, Chiou LL, Liang JD, Yang PC, Huang GT, Sheu JC (2005) EMP-1 is a junctional protein in a liver stem cell line and in the liver. Biochem Biophys Res Commun 334:996–1003

    Article  CAS  PubMed  Google Scholar 

  • Lock JG, Wehrle-Haller B, Stromblad S (2008) Cell–matrix adhesion complexes: master control machinery of cell migration. Semin Cancer Biol 18:65–76

    Article  CAS  PubMed  Google Scholar 

  • Lowes KN, Croager EJ, Olynyk JK, Abraham LJ, Yeoh GC (2003) Oval cell-mediated liver regeneration: Role of cytokines and growth factors. J Gastroenterol Hepatol 18:4–12

    Article  CAS  PubMed  Google Scholar 

  • Mavier P, Martin N, Couchie D, Preaux AM, Laperche Y, Zafrani ES (2004) Expression of stromal cell-derived factor-1 and of its receptor CXCR4 in liver regeneration from oval cells in rat. Am J Pathol 165:1969–1977

    CAS  PubMed  Google Scholar 

  • Michalopoulos GK, DeFrances MC (1997) Liver regeneration. Science 276:60–66

    Article  CAS  PubMed  Google Scholar 

  • Nguyen LN, Furuya MH, Wolfraim LA, Nguyen AP, Holdren MS, Campbell JS, Knight B, Yeoh GC, Fausto N, Parks WT (2007) Transforming growth factor-beta differentially regulates oval cell and hepatocyte proliferation. Hepatology 45:31–41

    Article  CAS  PubMed  Google Scholar 

  • Omori N, Omori M, Evarts RP, Teramoto T, Miller MJ, Hoang TN, Thorgeirsson SS (1997) Partial cloning of rat CD34 cDNA and expression during stem cell-dependent liver regeneration in the adult rat. Hepatology 26:720–727

    Article  CAS  PubMed  Google Scholar 

  • Paku S, Nagy P, Kopper L, Thorgeirsson SS (2004) 2-Acetylaminofluorene dose-dependent differentiation of rat oval cells into hepatocytes: confocal and electron microscopic studies. Hepatology 39:1353–1361

    Article  CAS  PubMed  Google Scholar 

  • Pi L, Oh SH, Shupe T, Petersen BE (2005) Role of connective tissue growth factor in oval cell response during liver regeneration after 2-AAF/PHx in rats. Gastroenterology 128:2077–2088

    Article  CAS  PubMed  Google Scholar 

  • Pi L, Ding X, Jorgensen M, Pan JJ, Oh SH, Pintilie D, Brown A, Song WY, Petersen BE (2008) Connective tissue growth factor with a novel fibronectin binding site promotes cell adhesion and migration during rat oval cell activation. Hepatology 47:996–1004

    Article  CAS  PubMed  Google Scholar 

  • Ponta H, Sherman L, Herrlich PA (2003) CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 4:33–45

    Article  CAS  PubMed  Google Scholar 

  • Preisegger KH, Factor VM, Fuchsbichler A, Stumptner C, Denk H, Thorgeirsson SS (1999) Atypical ductular proliferation and its inhibition by transforming growth factor beta1 in the 3, 5-diethoxycarbonyl-1, 4-dihydrocollidine mouse model for chronic alcoholic liver disease. Lab Invest 79:103–109

    CAS  PubMed  Google Scholar 

  • Sarraf C, Lalani EN, Golding M, Anilkumar TV, Poulsom R, Alison M (1994) Cell behavior in the acetylaminofluorene-treated regenerating rat liver. Light and electron microscopic observations. Am J Pathol 145:1114–1126

    CAS  PubMed  Google Scholar 

  • Sell S (1998) Comparison of liver progenitor cells in human atypical ductular reactions with those seen in experimental models of liver injury. Hepatology 27:317–331

    Article  CAS  PubMed  Google Scholar 

  • Sell S (2001) Heterogeneity and plasticity of hepatocyte lineage cells. Hepatology 33:738–750

    Article  CAS  PubMed  Google Scholar 

  • Sherman L, Sleeman J, Herrlich P, Ponta H (1994) Hyaluronate receptors: key players in growth, differentiation, migration and tumor progression. Curr Opin Cell Biol 6:726–733

    Article  CAS  PubMed  Google Scholar 

  • Sternlicht MD, Werb Z (2001) How matrix metalloproteinases regulate cell behavior. Ann Rev Cell Dev Biol 17:463–516

    Article  CAS  Google Scholar 

  • Tanimizu N, Tsujimura T, Takahide K, Kodama T, Nakamura K, Miyajima A (2004) Expression of Dlk/Pref-1 defines a subpopulation in the oval cell compartment of rat liver. Gene Expr Patterns 5:209–218

    Article  CAS  PubMed  Google Scholar 

  • Theise ND, Saxena R, Portmann BC, Thung SN, Yee H, Chiriboga L, Kumar A, Crawford JM (1999) The canals of Hering and hepatic stem cells in humans. Hepatology 30:1425–1433

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Foster M, Al-Dhalimy M, Lagasse E, Finegold M, Grompe M (2003) The origin and liver repopulating capacity of murine oval cells. Proc Natl Acad Sci USA 100(Suppl 1):11881–11888

    Article  CAS  PubMed  Google Scholar 

  • Yano Y, Hayashi Y, Teramoto T, Nakaji M, Nagy P, Ninomiya T, Wada A, Hirai M, Kim SR, Seo Y, Yoon S, Kasuga M (2004) Apoptotic pathway related to oval cell proliferation. J Gastroenterol Hepatol 19:866–872

    Article  CAS  PubMed  Google Scholar 

  • Yovchev MI, Grozdanov PN, Joseph B, Gupta S, Dabeva MD (2007) Novel hepatic progenitor cell surface markers in the adult rat liver. Hepatology 45:139–149

    Article  CAS  PubMed  Google Scholar 

  • Yovchev MI, Grozdanov PN, Zhou H, Racherla H, Guha C, Dabeva MD (2008) Identification of adult hepatic progenitor cells capable of repopulating injured rat liver. Hepatology 47:636–647

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

These studies were supported by grants from National Science Council (95-2314-B-002-099 and 96-2321-B-002-024-MY3), Executive Yuan, Taiwan, and from National Taiwan University (97R0066-42), and also partly supported by Liver Disease Prevention & Treatment Research Foundation, Taiwan.

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Authors and Affiliations

  1. The Graduate Institute of Applied Science and Engineering, Fu-Jen Catholic University, Taipei, Taiwan

    Chien-Chang Chiu

  2. Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, 100, Taiwan

    Jin-Chuan Sheu, Chien-Hung Chen, Cha-Ze Lee, Guan-Tarn Huang & Hsuan-Shu Lee

  3. Liver Disease Prevention and Treatment Research Foundation, Taipei, Taiwan

    Ling-Ling Chiou

  4. Department of Life Science, Fu-Jen Catholic University, 510 Chung Cheng Rd, Hsinchuang, Taipei, 24205, Taiwan

    Shiu-Huey Chou

  5. Institute of Biotechnology, College of Bio-Resources and Agriculture, National Taiwan University, 4F., No. 81, Chang-Xing St., Taipei, 106, Taiwan

    Hsuan-Shu Lee

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  1. Chien-Chang Chiu
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  2. Jin-Chuan Sheu
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  3. Chien-Hung Chen
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  4. Cha-Ze Lee
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  5. Ling-Ling Chiou
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  6. Shiu-Huey Chou
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  7. Guan-Tarn Huang
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  8. Hsuan-Shu Lee
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Correspondence to Shiu-Huey Chou, Guan-Tarn Huang or Hsuan-Shu Lee.

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Chiu, CC., Sheu, JC., Chen, CH. et al. Global gene expression profiling reveals a key role of CD44 in hepatic oval-cell reaction after 2-AAF/CCl4 injury in rodents. Histochem Cell Biol 132, 479–489 (2009). https://doi.org/10.1007/s00418-009-0634-9

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  • DOI: https://doi.org/10.1007/s00418-009-0634-9

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