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Journal of Molecular Histology

, Volume 39, Issue 4, pp 463–468 | Cite as

Immunohistochemical evaluation of hepatic oval cell activation and differentiation toward pancreatic beta-cell phenotype in streptozotocin-induced diabetic mice

  • M. Vorobeychik
  • K. Bloch
  • R. Zemel
  • L. Bachmetov
  • R. Tur-Kaspa
  • P. Vardi
Brief Communication

Abstract

Oval cell (OvCs) involvement in regeneration is a well known phenomenon in models of liver injury, however, the activation of these cells following streptozotocin (STZ)-induced diabetes has not been studied yet. Differentiation of liver cells toward insulin-producing cells in diabetes has been reported, but the cell phenotype is still unclear. The aim of the present study was to confirm by immunohistochemical analysis, the activation of OvCs and their ability to express pancreatic beta-cell phenotype in STZ-induced diabetic mice. Using specific anti-A6 antibodies for mouse OvCs, we found a three-fold increase in periportal number and two-fold higher density of OvCs in diabetic livers, when compared to controls. Unlike non-diabetic controls, double staining technique showed co-localization of A6 and proinsulin in the cytoplasm of OvCs of diabetic animals, but no insulin staining was detected, probably reflecting the premature character of OvCs differentiation toward beta-cell-like phenotype. These data add valuable information concerning the nature and the stage of functional maturity of liver cells undergoing differentiation toward beta-cell phenotype in STZ-induced diabetic animals.

Keywords

Diabetes Hepatic oval cells A6 antigen Proinsulin 

Notes

Acknowledgments

The authors thank Dr. Valentina Factor (National Institute of Health, USA) for kindly providing antibodies to A6 antigen and Sara Dominitz for editorial help. This work was supported in part by a grant from the Research Foundation of Tel Aviv University (#0601563121). MV is a recipient of a scholarship from the Legacy Heritage Fund, Developmental and Cell Biology Department, Sackler Faculty of Medicine, Tel Aviv University, Israel.

References

  1. Akhurst B, Croager EJ, Farley-Roche CA et al (2001) A modified choline-deficient, ethionine-supplemented diet protocol effectively induces oval cells in mouse liver. Hepatology 34:519–522. doi: 10.1053/jhep.2001.26751 PubMedCrossRefGoogle Scholar
  2. Andican G, Burçak G (2005) Oxidative damage to nuclear DNA in streptozotocin-diabetic rat liver. Clin Exp Pharmacol Physiol 32:663–666. doi: 10.1111/j.0305-1870.2005.04247.x PubMedCrossRefGoogle Scholar
  3. Bird TG, Lorenzini S, Forbes S (2008) Activation of stem cells in hepatic diseases. Cell Tissue Res 331:283–300. doi: 10.1007/s00441-007-0542-z PubMedCrossRefGoogle Scholar
  4. Deutsch G, Jung J, Zheng M et al (2001) A bipotential precursor population for pancreas and liver within the embryonic endoderm. Development 128:871–881PubMedGoogle Scholar
  5. Dorrell C, Grompe M (2005) Liver repair by intra- and extrahepatic progenitors. Stem Cell Rev 1:61–64. doi: 10.1385/SCR:1:1:061 PubMedCrossRefGoogle Scholar
  6. Engelhardt N, Factor V, Yasova A et al (1990) Common antigens of mouse oval and biliary epithelial cells. Expression on newly formed hepatocytes. Differentiation 45:29–37. doi: 10.1111/j.1432-0436.1990.tb00453.x PubMedCrossRefGoogle Scholar
  7. Jelnes P, Santoni-Rugiu E, Rasmussen M et al (2007) Remarkable heterogeneity displayed by oval cells in rat and mouse models of stem cell-mediated liver regeneration. Hepatology 45:1462–1470. doi: 10.1002/hep.21569 PubMedCrossRefGoogle Scholar
  8. Kim S, Shin J, Kim H et al (2007) Streptozotocin-induced diabetes can be reversed by hepatic oval cell activation through hepatic transdifferentiation and pancreatic islet regeneration. Lab Invest 87:702–712. doi: 10.1038/labinvest.3700561 PubMedCrossRefGoogle Scholar
  9. Kofman A, Morgan G, Kirschenbaum A et al (2005) Dose- and time-dependent oval cell reaction in acetaminophen-induced murine liver injury. Hepatology 41:1252–1261. doi: 10.1002/hep.20696 PubMedCrossRefGoogle Scholar
  10. Kojima H, Fujimiya M, Matsumura K et al (2004) Extrapancreatic insulin-producing cells in multiple organs in diabetes. Proc Natl Acad Sci USA 101:2458–2463. doi: 10.1073/pnas.0308690100 PubMedCrossRefGoogle Scholar
  11. Kojima H, Fujimiya M, Terashima T et al (2006) Extrapancreatic proinsulin/insulin-expressing cells in diabetes mellitus: is history repeating itself? Endocr J 53:715–722. doi: 10.1507/endocrj.KR-84 PubMedCrossRefGoogle Scholar
  12. Okamoto H, Takasawa S (2002) Recent advances in the Okamoto model: the CD38-cyclic ADP-ribose signal system and the regenerating gene protein (Reg)-Reg receptor system in beta-cells. Diabetes 51:462–473. doi: 10.2337/diabetes.51.2007.S462 CrossRefGoogle Scholar
  13. Petersen BE, Goff JP, Greenberger JS, Michalopoulos GK (1998) Hepatic oval cells express the hematopoietic stem cell marker Thy-1 in the rat. Hepatology 27:433–445. doi: 10.1002/hep.510270218 PubMedCrossRefGoogle Scholar
  14. Petersen BE, Grossbard B, Hatch H et al (2003) Mouse A6-positive hepatic oval cells also express several hematopoietic stem cell markers. Hepatology 37:632–640. doi: 10.1053/jhep.2003.50104 PubMedCrossRefGoogle Scholar
  15. Rhee S, Jeong Y, Choi J (2005) Effects of vitamin E on phospholipase A 2 activity and oxidative damage to the liver in streptozotocin-induced diabetic rats. Ann Nutr Metab 49:392–396. doi: 10.1159/000088930 PubMedCrossRefGoogle Scholar
  16. Schnedl WJ, Ferber S, Johnson JH, Newgard CB (1994) STZ transport and cytotoxicity. Specific enhancement in GLUT2-expressing cells. Diabetes 43:1326–1333. doi: 10.2337/diabetes.43.11.1326 PubMedCrossRefGoogle Scholar
  17. Thorens B (1996) Glucose transporters in the regulation of intestinal, renal and liver glucose fluxes. Am J Physiol 270:G541–G553PubMedGoogle Scholar
  18. Yang L, Li S, Hatch H et al (2002) In vitro trans-differentation of adult hepatic stem cells into pancreatic endocrine hormone-producing cells. Proc Natl Acad Sci USA 99:8078–8083. doi: 10.1073/pnas.122210699 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • M. Vorobeychik
    • 1
    • 2
  • K. Bloch
    • 1
  • R. Zemel
    • 2
  • L. Bachmetov
    • 2
  • R. Tur-Kaspa
    • 2
  • P. Vardi
    • 1
  1. 1.Diabetes and Obesity Research Laboratory, Felsenstein Medical Research Center, Sackler Faculty of MedicineTel-Aviv UniversityPetah TikvaIsrael
  2. 2.Molecular Hepatology Research Laboratory, Felsenstein Medical Research Center, Sackler Faculty of MedicineTel-Aviv UniversityPetah TikvaIsrael

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