Skip to main content

Advertisement

SpringerLink
Log in

Stage-specific regulation of adhesion molecule expression segregates epithelial stem/progenitor cells in fetal and adult human livers

  • Original Research
  • Published:
Hepatology International Aims and scope Submit manuscript

Abstract

Purpose

Regulated expression of cell adhesion molecules could be critical in the proliferation, sequestration, and maintenance of stem/progenitor cells. Therefore, we determined fetal and adult stage-specific roles of cell adhesion in liver cell compartments.

Methods

We performed immunostaining for the adhesion molecules, E-cadherin and Ep-CAM, associated proteins, β-catenin and α-actinin, hepatobiliary markers, albumin, α-fetoprotein, and cytokeratin-19, and the proliferation marker, Ki-67. Expression of albumin was verified by in situ mRNA hybridization.

Results

In the fetal liver, hepatoblasts showed extensive proliferation with wide expression of E-cadherin, β-catenin, and α-actinin, although Ep-CAM was expressed in these cells less intensely and focally in the cell membrane to indicate weak cell adhesion. Hepatoblasts in ductal plate and bile ducts showed less proliferation and Ep-CAM was intensely expressed in these cells throughout the cell membrane, indicating strong adhesion. In some ductal plate cells, β-catenin was additionally in the cytoplasm and nucleus, suggesting active cell signaling by adhesion molecules. In adult livers, cells were no longer proliferating and E-cadherin, β-catenin, and α-actinin were expressed in hepatocytes throughout, whereas Ep-CAM was expressed in only bile duct cells. Some cells in ductal structures of the adult liver with Ep-CAM coexpressed albumin and cytokeratin-19, indicating persistence of fetal-like stem/progenitor cells.

Conclusions

Regulated expression of Ep-CAM supported proliferation in fetal hepatoblasts through weak adhesion and helped in biliary morphogenesis by promoting stronger adhesion in hepatoblasts during this process. Restriction of Ep-CAM expression to bile ducts in the adult liver presumably facilitated sequestration of stem/progenitor cells. This stage-specific and cell compartment-related regulation of adhesion molecules should be relevant for defining how liver stem/progenitor cells enter, exit, and remain in hepatic niches during both health and disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Lemaigre F, Zaret KS. Liver development update: new embryo models, cell lineage control, and morphogenesis. Curr Opin Genet Dev 2004;14:582–90.

    Article  PubMed  CAS  Google Scholar 

  2. Cleaver O, Melton DA. Endothelial signaling during development. Nat Med 2003;9:661–8.

    Article  PubMed  CAS  Google Scholar 

  3. Nelson WJ, Nusse R. Convergence of Wnt, beta-catenin, and cadherin pathways. Science 2004;303:1483–7.

    Article  PubMed  CAS  Google Scholar 

  4. Hotchin NA, Gandarillas A, Watt FM. Regulation of cell surface beta 1 integrin levels during keratinocyte terminal differentiation. J Cell Biol 1995;128:1209–19.

    Article  PubMed  CAS  Google Scholar 

  5. Kirman I, Jenkins D, Fowler R, Whelan RL. Naturally occurring antibodies to epithelial cell adhesion molecule (EpCAM). Dig Dis Sci 2003;48:2306–9.

    Article  PubMed  CAS  Google Scholar 

  6. Winter MJ, Nagelkerken B, Mertens AE, Rees-Bakker HA, Briaire-de Bruijn IH, Litvinov SV. Expression of Ep-CAM shifts the state of cadherin-mediated adhesions from strong to weak. Exp Cell Res 2003;285:50–8.

    Article  PubMed  CAS  Google Scholar 

  7. Breuhahn K, Baeuerle PA, Peters M, Prang N, Tox U, Kohne-Volland R, et al. Expression of epithelial cellular adhesion molecule (Ep-CAM) in chronic (necro-)inflammatory liver diseases and hepatocellular carcinoma. Hepatol Res 2006;34:50–6.

    Article  PubMed  CAS  Google Scholar 

  8. Litvinov SV, van Driel W, van Rhijn CM, Bakker HA, van Krieken H, Fleuren GJ, et al. Expression of Ep-CAM in cervical squamous epithelia correlates with an increased proliferation and the disappearance of markers for terminal differentiation. Am J Pathol 1996;148:865–75.

    PubMed  CAS  Google Scholar 

  9. Otey CA, Carpen O. Alpha-actinin revisited: a fresh look at an old player. Cell Motil Cytoskeleton 2004;58:104–11.

    Article  PubMed  CAS  Google Scholar 

  10. Sancho E, Batlle E, Clevers H. Live and let die in the intestinal epithelium. Curr Opin Cell Biol 2003;15:763–70.

    Article  PubMed  CAS  Google Scholar 

  11. Badve S, Logdberg L, Sokhi R, Sigal SH, Botros N, Chae S, et al. An antigen reacting with Das-1 monoclonal antibody is ontogenically regulated in diverse organs including liver and indicates sharing of developmental mechanisms among cell lineages. Pathobiology 2000;68:76–86.

    Article  PubMed  CAS  Google Scholar 

  12. Dan YY, Riehle KJ, Lazaro C, Teoh N, Haque J, Campbell JS, et al. Isolation of multipotent progenitor cells from human fetal liver capable of differentiating into liver and mesenchymal lineages. Proc Natl Acad Sci USA 2006;103:9912–7.

    Article  PubMed  CAS  Google Scholar 

  13. Malhi H, Irani AN, Gagandeep S, Gupta S. Isolation of human progenitor liver epithelial cells with extensive replication capacity and differentiation into mature hepatocytes. J Cell Sci 2002;115:2679–88.

    PubMed  CAS  Google Scholar 

  14. Alison MR, Vig P, Russo F, Bigger BW, Amofah E, Themis M, et al. Hepatic stem cells: from inside and outside the liver? Cell Prolif 2004;37:1–21.

    Article  PubMed  CAS  Google Scholar 

  15. Fausto N. Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells. Hepatology 2004;39:1477–87.

    Article  PubMed  Google Scholar 

  16. Lemaigre FP. Development of the biliary tract. Mech Dev 2003;120:81–87.

    Article  PubMed  CAS  Google Scholar 

  17. Novikoff PM, Yam A, Oikawa I. Blast-like cell compartment in carcinogen-induced proliferating bile ductules. Am J Pathol 1996;148:1473–92.

    PubMed  CAS  Google Scholar 

  18. Saxena R, Theise N. Canals of Hering: recent insights and current knowledge. Semin Liver Dis 2004;24:43–8.

    Article  PubMed  Google Scholar 

  19. Sell S. Heterogeneity and plasticity of hepatocyte lineage cells. Hepatology 2001;33:738–50.

    Article  PubMed  CAS  Google Scholar 

  20. Litvinov SV, Winter MJ, Bakker HA, Briaire-de Bruijn IH, Prins F, Fleuren GJ, et al. Epithelial cell adhesion molecule (Ep-CAM) modulates cell-cell interactions mediated by classic cadherins. J Cell Biol 1997;139:1337–48.

    Article  PubMed  CAS  Google Scholar 

  21. Cho J, Joseph B, Sappal BS, Giri RK, Wang R, Ludlow J, et al. Analysis of the functional integrity of cryopreserved human liver cells including xenografting in immunodeficient mice to address suitability for clinical applications. Liver Int 2004;4:361–70.

    Article  Google Scholar 

  22. Dabeva MD, Shafritz DA. Activation, proliferation and differentiation of progenitor cells into hepatocytes in the d-galactosamine model of liver regeneration. Am J Pathol 1993; 143:1606–20.

    PubMed  CAS  Google Scholar 

  23. Munz M, Kieu C, Mack B, Schmitt B, Zeidler R, Gires O. The carcinoma-associated antigen EpCAM upregulates c-myc and induces cell proliferation. Oncogene 2004;23:5748–58.

    Article  PubMed  Google Scholar 

  24. de Boer CJ, van Krieken JH, Janssen-van Rhijn CM, Litvinov SV. Expression of Ep-CAM in normal, regenerating, metaplastic, and neoplastic liver. J Pathol 1999;188:201–6.

    Article  PubMed  Google Scholar 

  25. Yovchev MI, Grozdanov PN, Joseph B, Gupta S, Dabeva MD. Novel hepatic progenitor cell surface markers in the adult rat liver. Hepatology 2007;45:139–49.

    Article  PubMed  CAS  Google Scholar 

  26. Humphries MJ, Newham P. The structure of cell-adhesion molecules. Trends Cell Biol 1998;8:78–83.

    Article  PubMed  CAS  Google Scholar 

  27. Karecla PI, Green SJ, Bowden SJ, Coadwell J, Kilshaw PJ. Identification of a binding site for integrin alphaEbeta7 in the N-terminal domain of E-cadherin. J Biol Chem 1996;271:30909–15.

    Article  PubMed  CAS  Google Scholar 

  28. Couvelard A, Bringuier AF, Dauge MC, Nejjari M, Darai E, Benifla JL, et al. Expression of integrins during liver organogenesis in humans. Hepatology 1998;27:839–47.

    Article  PubMed  CAS  Google Scholar 

  29. Terada T, Ashida K, Kitamura Y, Matsunaga Y, Takashima K, Kato M, et al. Expression of epithelial-cadherin, alpha-catenin and beta-catenin during human intrahepatic bile duct development: a possible role in bile duct morphogenesis. J Hepatol 1998;28:263–9.

    Article  PubMed  CAS  Google Scholar 

  30. Ihara A, Koizumi H, Hashizume R, Uchikoshi T. Expression of epithelial cadherin and alpha- and beta-catenins in nontumoral livers and hepatocellular carcinomas. Hepatology 1996;23:1441–7.

    PubMed  CAS  Google Scholar 

  31. Scoazec JY. Adhesion molecules in normal human liver. Hepatogastroenterology 1996;43:1103–5.

    PubMed  CAS  Google Scholar 

  32. Van Den Heuvel MC, Slooff MJ, Visser L, Muller M, De Jong KP, Poppema S, et al. Expression of anti-OV6 antibody and anti-N-CAM antibody along the biliary line of normal and diseased human livers. Hepatology 2001;33:1387–93.

    Article  Google Scholar 

  33. Winter MJ, Nagtegaal ID, van Krieken JH, Litvinov SV. The epithelial cell adhesion molecule (Ep-CAM) as a morphoregulatory molecule is a tool in surgical pathology. Am J Pathol 2003;163:2139–48.

    PubMed  CAS  Google Scholar 

  34. Dorfman DM, Greisman HA, Shahsafaei A. Loss of expression of the WNT/beta-catenin-signaling pathway transcription factors lymphoid enhancer factor-1 (LEF-1) and T cell factor-1 (TCF-1) in a subset of peripheral T cell lymphomas. Am J Pathol 2003;162:1539–44.

    PubMed  CAS  Google Scholar 

  35. Hassan A, Yerian LM, Kuan SF, Xiao SY, Hart J, Wang HL. Immunohistochemical evaluation of adenomatous polyposis coli, beta-catenin, c-Myc, cyclin D1, p53, and retinoblastoma protein expression in syndromic and sporadic fundic gland polyps. Hum Pathol 2004;35:328–34.

    Article  PubMed  CAS  Google Scholar 

  36. Taniguchi K, Roberts LR, Aderca IN, Dong X, Qian C, Murphy LM, et al. Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Oncogene 2002;21:4863–71.

    Article  PubMed  CAS  Google Scholar 

  37. Tian YC, Phillips AO. Interaction between the transforming growth factor-beta type II receptor/Smad pathway and beta-catenin during transforming growth factor-beta1-mediated adherens junction disassembly. Am J Pathol 2002;160:1619–28.

    PubMed  CAS  Google Scholar 

  38. Espada J, Perez-Moreno M, Braga VM, Rodriguez-Viciana P, Cano A. H-Ras activation promotes cytoplasmic accumulation and phosphoinositide 3-OH kinase association of beta-catenin in epidermal keratinocytes. J Cell Biol 1999;146:967–80.

    Article  PubMed  CAS  Google Scholar 

  39. Morali OG, Delmas V, Moore R, Jeanney C, Thiery JP, Larue L. IGF-II induces rapid beta-catenin relocation to the nucleus during epithelium to mesenchyme transition. Oncogene 2001;20:4942–50.

    Article  PubMed  CAS  Google Scholar 

  40. Novak A, Hsu SC, Leung-Hagesteijn C, Radeva G, Papkoff J, Montesano R, et al. Cell adhesion and the integrin-linked kinase regulate the LEF-1 and beta-catenin signaling pathways. Proc Natl Acad Sci USA 1998;95:4374–9.

    Article  PubMed  CAS  Google Scholar 

  41. Micsenyi A, Tan X, Sneddon T, Luo JH, Michalopoulos GK, Monga SP. Beta-catenin is temporally regulated during normal liver development. Gastroenterology 2004;126:1134–46.

    Article  PubMed  CAS  Google Scholar 

  42. Hunter MP, Wilson CM, Jiang X, Cong R, Vasavada H, Kaestner KH, et al. The homeobox gene Hhex is essential for proper hepatoblast differentiation and bile duct morphogenesis. Dev Biol 2007;308:355–67.

    Article  PubMed  CAS  Google Scholar 

  43. Fabris L, Cadamuro M, Guido M, Spirli C, Fiorotto R, Colledan M, et al. Analysis of liver repair mechanisms in Alagille syndrome and biliary atresia reveals a role for notch signaling. Am J Pathol 2007;171:641–53.

    Google Scholar 

  44. Kosterink JG, McLaughlin PM, Lub-de Hooge MN, Hendrikse HH, van Zanten J, van Garderen E, et al. Biodistribution studies of epithelial cell adhesion molecule (EpCAM)-directed monoclonal antibodies in the EpCAM-transgenic mouse tumor model. J Immunol 2007;179:1362–8.

    PubMed  CAS  Google Scholar 

  45. Crosby HA, Hubscher SG, Joplin RE, Kelly DA, Strain AJ. Immunolocalization of OV-6, a putative progenitor cell marker in human fetal and diseased pediatric liver. Hepatology 1998;28:980–5.

    Article  PubMed  CAS  Google Scholar 

  46. Haruna Y, Saito K, Spaulding S, Nalesnik MA, Gerber MA. Identification of bipotential progenitor cells in human liver development. Hepatology 1996;23:476–81.

    Article  PubMed  CAS  Google Scholar 

  47. Dan YY, Riehle KJ, Lazaro C, Teoh N, Haque J, Campbell JS, et al. Isolation of multipotent progenitor cells from human fetal liver capable of differentiating into liver and mesenchymal lineages. Proc Natl Acad Sci USA 2006;103:9912–7.

    Article  PubMed  CAS  Google Scholar 

  48. Hackney JA, Charbord P, Brunk BP, Stoeckert CJ, Lemischka IR, Moore KA. A molecular profile of a hematopoietic stem cell niche. Proc Natl Acad Sci USA 2002;99:13061–6.

    Article  PubMed  CAS  Google Scholar 

  49. Tan X, Apte U, Micsenyi A, Kotsagrelos E, Luo JH, Ranganathan S, et al. Epidermal growth factor receptor: a novel target of the Wnt/beta-catenin pathway in liver. Gastroenterology 2005;129:285–302.

    Article  PubMed  CAS  Google Scholar 

  50. Yang S, Koteish A, Lin H, Huang J, Roskams T, Dawson V, et al. Oval cells compensate for damage and replicative senescence of mature hepatocytes in mice with fatty liver disease. Hepatology 2004;39:403–11.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported in part by NIH grants R01 DK46952, P01 DK52956, and P20 GM075037

Author information

Authors and Affiliations

  1. Departments of Medicine and Pathology, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Ullmann 625, 1300 Morris Park Avenue, Bronx, NY, 10461, USA

    Mari Inada, Daniel Benten, Kang Cheng, Brigid Joseph, Ekaterine Berishvili, Mariana Dabeva & Sanjeev Gupta

  2. Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan

    Mari Inada

  3. Department of Pathology, Indiana University School of Medicine, Indianapolis, IN, USA

    Sunil Badve

  4. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA

    Lennart Logdberg

Authors
  1. Mari Inada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel Benten
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kang Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Brigid Joseph
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ekaterine Berishvili
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sunil Badve
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lennart Logdberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mariana Dabeva
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sanjeev Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sanjeev Gupta.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Inada, M., Benten, D., Cheng, K. et al. Stage-specific regulation of adhesion molecule expression segregates epithelial stem/progenitor cells in fetal and adult human livers. Hepatol Int 2, 50–62 (2008). https://doi.org/10.1007/s12072-007-9023-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12072-007-9023-4

Keywords

Search

Navigation