Skip to main content
SpringerLink
Log in

Stem cells of the liver

  • Review
  • Published:
Medical Electron Microscopy Aims and scope Submit manuscript

Abstract

Liver regeneration can be accomplished either by the entry of normally proliferatively quiescent, differentiated hepatocytes into the cell cycle or, if hepatocyte regeneration is impaired, by bile ductular cells that migrate centrifugally from the portal tracts before differentiating into hepatocytes. These ductal cells are called oval cells, and their emergence when hepatocyte regeneration is defective has led to the conclusion that they are the progeny of facultative stem cells. Oval cells are of great biological interest because they may be the progenitor cells of both hepatocellular carcinomas and cholangiocarcinomas; furthermore, they could be useful vehicles for ex vivo gene therapy for the correction of inborn errors of metabolism.

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

Similar content being viewed by others

References

  1. Shiojiri N, Lemire JM, Fausto N (1991) Cell lineages and oval cell progenitors in rat liver development. Cancer Res 51:2611–2620

    Google Scholar 

  2. Van-Eyken P, Sciot R, Callea F, Van der Steen K, Moerman P, Desmet VJ (1988) The development of the intrahepatic bile ducts in man: a keratin-immunohistochemical study. Hepatology 8:1586–1595

    Google Scholar 

  3. Potten CS, Booth C, Pritchard DM (1997) The intestinal epithelial stem cell: the mucosal governor. Int J Exp Pathol 78:219–243

    Google Scholar 

  4. Zajicek G, Oren J, Weinreb M (1985) The streaming liver. Liver 5:293–300

    Google Scholar 

  5. Correspondence (1995) Do livers “stream”? Am J Pathol 146:772–776

    Google Scholar 

  6. Grisham JW (1994) Migration of hepatocytes along hepatic plates and stem cell-fed hepatocyte lineages. Am J Pathol 144:849–854

    Google Scholar 

  7. Bralet MP, Branchereau S, Brechot C, Ferry N (1994) Cell lineage study in the liver using retroviral mediated gene transfer. Evidence against the streaming of hepatocytes in normal liver. Am J Pathol 144:896–905

    Google Scholar 

  8. Wright N, Alison M (1984) The conditional renewal populations: the liver. In: The biology of epithelial cell populations, vol 2. Clarendon Press, Oxford, pp 873–980

    Google Scholar 

  9. Alison MR (1986) Regulation of liver growth. Physiol Rev 66:499–541

    Google Scholar 

  10. Gerlach C, Sakkab DY, Scholzen T, Dassler R, Alison MR, Gerdes J (1997) Ki-67 expression during rat liver regeneration after partial hepatectomy. Hepatology 26:573–578

    Google Scholar 

  11. Opie EI (1944) The pathogenesis of tumours of the liver produced by butter yellow. J Exp Med 80:231–246

    Google Scholar 

  12. Farber E (1955) Similarities in the sequences of early histological changes induced in the liver of the rat by ethionine, 2-acetylaminofluorene, and 3-methyl-4-dimethylaminoazobenzene. Cancer Res 16:142–148

    Google Scholar 

  13. Wilson J, Leduc EH (1958) Role of cholangioles in restoration of the liver of the mouse after dietary injury. J Pathol Bacteriol 76:441–449

    Google Scholar 

  14. Alison M, Golding M, Lalani E-N, Nagy P, Thorgeirsson S, Sarraf C (1997) Wholesale hepatocytic differentiation in the rat from ductular oval cells, the progeny of biliary stem cells. J Hepatol 26:343–352

    Google Scholar 

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

    Google Scholar 

  16. Alison MR, Golding MHC, Sarraf CE (1996) Pluripotential liver stem cells: facultative stem cells located in the biliary tree. Cell Prolif 29:373–402

    Google Scholar 

  17. Evarts RP, Nagy P, Marsden E, Thorgeirsson SS (1987) A precursor-product relationship exists between oval cells and hepatocytes in rat liver. Carcinogenesis (Oxf) 8:1737–1740

    Google Scholar 

  18. 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

    Google Scholar 

  19. Golding M, Sarraf CE, Lalani E-N, Anilkumar TV, Edwards RJ, Nagy P, Thorgeirsson SS, Alison MR (1995) Oval cell differentiation into hepatocytes in the acetylaminofluorene-treated regenerating rat liver. Hepatology 22:1243–1253

    Google Scholar 

  20. Sarraf CE, Lalani F-N, Golding M, Anilkumar TV, Poulsom R, Alison MR (1994) Cell behaviour in the acetylaminofluorenetreated regenerating rat liver. Light and microscopic observations. Am J Pathol 145:1114–1126

    Google Scholar 

  21. Yasui O, Miura N, Terada K, Kawarada Y, Koyama K, Sugiyama T (1997) Isolation of oval cells from Long-Evans cinnamon rats and their transformation into hepatocytes in vivo in the rat liver. Hepatology 25:329–334

    Google Scholar 

  22. Anilkumar TV, Golding M, Edwards RJ, Lalani E-N, Sarraf CE, Alison MR (1995) The resistant hepatocyte model of carcinogenesis in the rat: the apparent independent development of oval cell proliferation and early nodules. Carcinogenesis (Oxf) 16:845–853

    Google Scholar 

  23. Novikoff PM, Yam A, Oikawa I (1996) Blast-like cell compartment in carcinogen-induced proliferating bile ductules. Am J Pathol 14:1473–1492

    Google Scholar 

  24. Alpini G, Roberts S, Kuntz SM, Ueno Y, Gubba S, Podila PV, LeSage G, LaRusso NF (1996) Morphological, molecular, and functional heterogeneity of cholangiocytes from normal rat liver. Gastroenterology 110:1636–1643

    Google Scholar 

  25. Park CM, Cha IH, Chung KB, Suh WH, Lee CH, Choi SY, Chae YS (1991) Hepatocellular carcinoma in extrahepatic bile ducts. Acta Radiol (Stockh) 32:34–36

    Google Scholar 

  26. Sirica AE, Gainey TW, Mumaw VR (1994) Ductular hepatocytes. Evidence for a bile ductular cell origin in furan-treated rats. Am J Pathol 145:375–383

    Google Scholar 

  27. Factor VM, Radaeva SA, Thorgeirsson SS (1994) Origin and fate of oval cells in dipin-induced hepatocarcinogenesis in the mouse. Am J Pathol 145:409–422

    Google Scholar 

  28. Hiruma M, Seki A, Ono A, Kurihara T (1993) Early hepatic lesions with marked glandular structures induced in rats by 0.1% ethionine in a choline deficient diet. Jikken Dobutsu 42:197–201

    Google Scholar 

  29. Wu H, Wade M, Krall L, Grisham J, Xiong Y, Vandyke T (1996) Targetedin vivo expression of the cyclin dependent kinase inhibitor p21 halts hepatocyte cell cycle progression, postnatal liver development, and regeneration. Genes Dev 10:245–260

    Google Scholar 

  30. Betto H, Kaneda K, Yamamoto T, Kojima A, Sakurai M (1996) Development of intralobular bile ductules after spontaneous hepatitis in Long-Evans mutant rats. Lab Invest 75:43–53

    Google Scholar 

  31. Petersen BE, Zajac VF, Michalopoulos GK (1997) Bile ductular damage induced by methylene dianiline inhibits oval cell activation. Am J Pathol 151:905–909

    Google Scholar 

  32. Bisgaard HC, Nagy P, Santonirugiu E, Thorgeirsson SS (1996) Proliferation, apoptosis, and induction of hepatic transcription factors are characteristics of the early response of biliary epithelial (oval) cells to chemical carcinogens. Hepatology 23:62–70

    Google Scholar 

  33. Omori M, Evarts RP, Omori N, Hu Z, Marsden ER, Thorgeirsson SS (1997) Expression of alpha-fetoprotein and stem cell factor/c-kit system in bile duct ligated young rats. Hepatology 25:1115–1122

    Google Scholar 

  34. Hendrix MJC, Seftor EA, Seftor REB, Trevor KT (1997) Experimental co-expression of vimentin and keratin intermediate filaments in human breast cancer cells results in phenotypic interconversion and increased invasive behavior. Am J Pathol 150:483–495

    Google Scholar 

  35. Pagan R, Llobera M, Vilaro S (1995) Epithelial-mesenchymal transition in cultured neonatal hepatocytes. Hepatology 21:820–831

    Google Scholar 

  36. Pagan R, Martin I, Llobera M, Vilaro S (1997) Epithelialmesenchymal transition of cultured rat neonatal hepatocytes is differentially regulated in response to epidermal growth factor and dimethyl sulfoxide. Hepatology 25:598–606

    Google Scholar 

  37. Alison MR, Poulsom R, Jeffery R, Anilkumar TV, Jagoe R, Sarraf CE (1993) Expression of hepatocyte growth factor mRNA during oval cell activation in the rat liver. J Pathol 171:291–299

    Google Scholar 

  38. Thorgeirsson SS, Evarts RP, Bisgaard HC, Fujio K, Hu Z (1993) Hepatic stem cell compartment: activation and lineage commitment. Proc Soc Exp Biol Med 204:253–260

    Google Scholar 

  39. Evarts RP, Nakatsukasa H, Marsden ER, Hsia CC, Dunsford HA, Thorgeirsson SS (1990) Cellular and molecular changes in the early stages of chemical hepatocarcinogenesis in the rat. Cancer Res 50:3439–3444

    Google Scholar 

  40. Terada T, Okada Y, Nakanuma Y (1995) Expression of matrix proteinases during human intrahepatic bile duct development. A possible role in biliary cell migration. Am J Pathol 147:1207–1213

    Google Scholar 

  41. Coleman WB, Wennerberg AE, Smith GJ, Grisham JW (1993) Regulation of the differentiation of diploid and some aneuploid rat liver epithelial (stemlike) cells by the hepatic microenvironment. Am J Pathol 142:1373–1382

    Google Scholar 

  42. Roskams T, Campos RV, Drucker DJ, Desmet VJ (1993) Reactive human bile ductules express parathyroid hormone-related peptide. Histopathology (Oxf) 23:11–19

    Google Scholar 

  43. Roskams T, Willems M, Campos RV, Drucker DJ, Yap SH, Desmet VJ (1993) Parathyroid hormone-related peptide expression in primary and metastatic liver tumours. Histopathology (Oxf) 23:519–525

    Google Scholar 

  44. Roskams T, Moshage H, Depla E, Willems M, Desmet V, Yap P (1995) Parathyroid hormone-related peptide is expressed and rapidly inducible in human liver cell cultures that have a bile duct phenotype. J Hepatol 23:160–165

    Google Scholar 

  45. Milani S, Herbst H, Schuppan D, Stein H, Surrenti C (1991) Transforming growth factors beta 1 and beta 2 are differentially expressed in fibrotic liver disease. Am J Pathol 139:1221–1229

    Google Scholar 

  46. Nagy P, Evarts RP, McMahon JB, Thorgeirsson SS (1989) Role of TGF-beta in normal differentiation and oncogenesis in rat liver. Mol Carcinog 2:345–354

    Google Scholar 

  47. 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

    Google Scholar 

  48. Alison MR, Nasim M, Anilkumar TV, Sarraf CE (1993) Transforming growth factor-α immunoreactivity in a variety of epithelial tissues. Cell Prolif 26:449–460

    Google Scholar 

  49. Evarts RP, Nakatsukasa H, Marsden ER, Hu Z, Thorgeirsson SS (1992) Expression of transforming growth factor-alpha in regenerating liver and during hepatic differentiation. Mol Carcinog 5:25–31

    Google Scholar 

  50. 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

    Google Scholar 

  51. Tatematsu M, Kaku T, Medline A, Farber E (1985) Intestinal metaplasia as a common option of oval cells in relation to cholangiofibrosis in liver of rats exposed to 2-acetylaminofluorene. Lab Invest 52:354–362

    Google Scholar 

  52. Elmore LW, Sirica AE (1993) “Intestinal-type” of adenocarcinoma preferentially induced in right/caudate liver lobes of rats treated with furan. Cancer Res 53:254–259

    Google Scholar 

  53. Karaki Y, Munakata S, Saeki T, Hirota S, Fujimaki M (1991) Appearance of a carcinoid-like pattern in rat hepatic tumors induced by 3′-methyl-4-dimethyl-aminoazobenzene. Jpn J Cancer Res 82:397–402

    Google Scholar 

  54. Terada T, Nakanuma Y (1993) Development of human intrahepatic peribiliary glands. Histological, keratin immunohistochemical, and mucus histochemical analyses. Lab Invest 68:261–269

    Google Scholar 

  55. Mitaka T, Norioka K, Nakamura T, Mochizuki Y (1993) Effects of mitogens and co-mitogens on the formation of small-cell colonies in primary cultures of rat hepatocytes. J Cell Physiol 157:461–468

    Google Scholar 

  56. Tateno C, Yoshizato K (1996) Long term cultivation of adult rat hepatocytes that undergo multiple cell divisions and express normal parenchymal phenotypes. Am J Pathol 148:383–392

    Google Scholar 

  57. Overturf K, Al-Dhalimy M, Ou CN, Finegold M, Grompe M (1997) Serial transplantation reveals the stem-like regenerative potential of adult mouse hepatocytes. Am J Pathol 151:1273–1280

    Google Scholar 

  58. Bralet MP, Calise D, Brechot C, Ferry N (1996) In vivo cell lineage analysis during chemical hepatocarcinogenesis using retroviralmediated gene transfer. Lab Invest 74:871–881

    Google Scholar 

  59. Steinberg P, Steinbrecher R, Radaeva S, Schirmacher P, Dienes HP, Oesch F, Bannasch P (1994) Oval cell lines OC/CDE 6 and OC/CDE 22 give rise to cholangio-cellular and undifferentiated carcinomas after transformation. Lab Invest 71:700–709

    Google Scholar 

  60. Enjoji M, Nakashima M, Honda M, Sakai H, Nawata H (1997) Hepatocytic phenotypes induced in sarcomatous cholangiocarcinoma cells treated with 5-azacytidine. Hepatology 26:288–294

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Histopathology Department, Division of Investigative Science, ICSM at Hammersmith Campus, Du Cane Road, W12 0NN, London, UK

    M. Alison, M. Golding, V. Emons, T. V. Anilkumar & C. Sarraf

Authors
  1. M. Alison
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Golding
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. V. Emons
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T. V. Anilkumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C. Sarraf
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Alison.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Alison, M., Golding, M., Emons, V. et al. Stem cells of the liver. Med Electron Microsc 31, 53–60 (1998). https://doi.org/10.1007/BF01557781

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01557781

Key Words

Search

Navigation