World Journal of Surgery

, Volume 31, Issue 4, pp 808–816 | Cite as

Platelets Promote Liver Regeneration in Early Period after Hepatectomy in Mice

  • Soichiro Murata
  • Nobuhiro Ohkohchi
  • Ryota Matsuo
  • Osamu Ikeda
  • Andriy Myronovych
  • Reiko Hoshi
Article

Abstract

Background

Platelets contain several growth factors, including platelet-derived growth factor and hepatocyte growth factor.

Materials and methods

We examined the effects of platelet increment on liver regeneration after 70% hepatectomy. Hepatectomies were carried out in male BALB/c mice, and subsequently divided into three groups: (i) untreated mice, (ii) thrombocytotic mice induced with thrombopoietin, and (iii) thrombocytopenic mice induced with anti-platelet antibody. Growth kinetics in the liver were analyzed as a function of the liver/body weight ratio, the mitotic index, the proliferating cell nuclear antigen labeling index and Ki-67 labeling index. Activation of signal transduction pathways relating to cell proliferation were examined, including the STAT3, Akt, and ERK1/2 pathways. Platelet accumulation in the residual liver was quantified by immunohistochemistry and transmission electron microscopy.

Results

In thrombocytotic and thrombocytopenic mice, liver/body weight ratios and Ki-67 labeling indices were significantly increased and significantly decreased, respectively, compared with untreated mice 48 hours post-hepatectomy. The Akt pathway was strongly activated, and platelet accumulation was significantly increased in thrombocytotic group 5 minutes post-hepatectomy compared with normal and thrombocytopenic groups. After hepatectomy platelets accumulated in the sinusoids of liver and promoted hepatocyte proliferation in early period after hepatectomy.

Conclusion

By increasing or decreasing the platelet, marked changes in liver regeneration can occur, due to differences in cellular signaling and mitosis.

Keywords

Hepatocyte Growth Factor Proliferate Cell Nuclear Antigen Liver Regeneration Sinusoidal Endothelial Cell Hepatocyte Proliferation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

The authors thank Dr. Kojima and Dr. Nagasawa, University of Tsukuba, Advanced Biomedical Applications, for providing the rat anti-mouse monoclonal antibody Pm-1. We also thank Kirin Brewery Co, Takasaki, Japan, for providing the PEG-rHuMGDF, and Professor M.Yamamoto, Center for Tsukuba Advanced Research Alliance, University of Tsukuba for helpful comments and suggestions. We also thank Dr. Jon Maher, Center for Tsukuba Advanced Research Alliance, University of Tsukuba for correcting English grammar.

References

  1. 1.
    Michalopoulos GK, DeFrances MC. Liver regeneration. Science 1997;276:60–66PubMedCrossRefGoogle Scholar
  2. 2.
    Fausto N. Liver regeneration. J Hepatol 2000;32:19–31PubMedCrossRefGoogle Scholar
  3. 3.
    Streetz KL, Luedde T, Manns MP, et al. Interlekin 6 and liver regeneration. Gut 2000;47:309–312PubMedCrossRefGoogle Scholar
  4. 4.
    Behrens A, Sibilia M, David JP, et al. Impaired postnatal hepatocyte proliferation and liver regeneration in mice lacking c-jun in the liver. EMBO J 2002;21:1782–1790PubMedCrossRefGoogle Scholar
  5. 5.
    DeAngelis RA, Kovalovich K, Cressman DE, et al. Normal liver regeneration in p50/ nuclear factor κB1 knockout mice. Hepatology 2001;33:915–924PubMedCrossRefGoogle Scholar
  6. 6.
    Li W, Liang X, Kellendonk C, et al. STAT3 contributes to mitogenic response of hepatocytes during liver regeneration. J Biol Chem 2002;277:28411–28417PubMedCrossRefGoogle Scholar
  7. 7.
    Spector MS, Auer KL, Jarvis WD, et al. Differential regulation of the mitogen-activated protein and stress-activated protein kinase cascades by adrenergic agonists in quiescent and regenerating adult rat hepatocytes. Mol Cell Biol 1997;17:3556–3565PubMedGoogle Scholar
  8. 8.
    Hong F, Nguyen VA, Shen X, et al. Rapid activation of protein kinase B/Akt has a key role in antiapoptotic signaling during liver regeneration. Biochem Biophys Res Commun 2000;279:974–979PubMedCrossRefGoogle Scholar
  9. 9.
    Albrecht JH, Hansen LK. Cyclin D1 promotes mitogen-independent cell cycle progression in hepatocytes. Cell Growth Differ 1999;10:397–404PubMedGoogle Scholar
  10. 10.
    Ueda J, Chijiwa K, Nakano K. Cyclin expression in the atrophying and proliferating lobes of the liver after portal vein branch ligation and hepatectomy in rats. J Surg Res 2004;120:89–96PubMedCrossRefGoogle Scholar
  11. 11.
    Borowiak M, Garratt AN, Wüstefeld T, et al. Met provides essential signals for liver regeneration. Proc Natl Acad Sci USA 2004;101:10608–10613PubMedCrossRefGoogle Scholar
  12. 12.
    Fausto N, Laird AD, Webber EM. Role of growth factors and cytokines in hepatic regeneration. FASEB J 1995;9:1527–1536PubMedGoogle Scholar
  13. 13.
    Akerman P, Cote P, Yang SQ, et al. Antibodies to tumor necrosis factor–α inhibit liver regeneration after partial hepatectomy. Am J Physiol 1992;263:G579–G585PubMedGoogle Scholar
  14. 14.
    Blindenbacher A, Wang X, Langer I, et al. Interleukin 6 is important for survival after partial hepatectomy in mice. Hepatology 2003;38:674–682PubMedCrossRefGoogle Scholar
  15. 15.
    Nakamura T, Teramoto H, Ichihara A. Purification and characterization of a growth factor from rat platelets for mature parenchymal hepatocytes in primary cultures. Proc Natl Acad Sci USA 1986;83:6489–6493PubMedCrossRefGoogle Scholar
  16. 16.
    Oka Y, Orth DN. Human plasma epidermal growth factor/β-urogastrone is associated with blood platelets. J Clin Invest 1983;72:249–259PubMedCrossRefGoogle Scholar
  17. 17.
    Lesurtel M, Graf R, Aleil B, et al. Platelet-derived serotonin mediates liver regeneration. Science 2006;312:104–107PubMedCrossRefGoogle Scholar
  18. 18.
    Murata S, Ohkohchi N, Abe T, et al. Platelets promote G1-S progression of liver regeneration after hepatectomy. In: Antoniou E, Vagianos C, Kouraklis G (editors). The 39th congress of the European Society for Surgical Research. Bologna, Italy, Medimond S.R.L., 2004. 107–112Google Scholar
  19. 19.
    Shibuya K, Akahori H, Takahashi K, et al. Multilineage hematopoietic recovery by a single injection of pegylated recombinant human megakaryocyte growth and development factor in myelosuppressed mice. Blood 1998;91:37–45PubMedGoogle Scholar
  20. 20.
    Skomorovski K, Harpak H, Ianovski A, et al. New TPO treatment schedules of increased safety and efficacy: pre-clinical validation of a thrombopoiesis simulation model. Br J Haematol 2003;123:683–691PubMedCrossRefGoogle Scholar
  21. 21.
    Nagata Y, Nagahisa H, Aida Y, et al. Thrombopoietin induces megakaryocyte differentiation in hematopoietic progenitor FDC-P2 cells. J Biol Chem 1995;270:19673–19675PubMedCrossRefGoogle Scholar
  22. 22.
    Nagata Y, Shozaki Y, Nagahisa H, et al. Serum thrombopoietin level is not regulated by transcription but by the total counts of both megakaryocytes and platelets during thrombocytopenia and thrombocytosis. Thromb Haemost 1997;77(5):808–814PubMedGoogle Scholar
  23. 23.
    Higgins GM, Anderson RM. Experimental pathology of the liver. Arch Pathol 1931;12:186–202Google Scholar
  24. 24.
    Selzner N, Selzner M, Odermatt B, et al. ICAM-1 triggers liver regeneration through leukocyte recruitment and Kupffer cell-dependent release of TNF-α/IL-6 in mice. Gastroenterology 2003;124:692–700PubMedCrossRefGoogle Scholar
  25. 25.
    Ozaki M, Haga S, Zhang H, et al. Inhibition of hypoxia/reoxygenetion-induced oxidative stress in HGF-stimulated antiapoptotic signaling: role of PI3-K and Akt kinase upon rac 1. Cell Death Differ 2003;10:508–515PubMedCrossRefGoogle Scholar
  26. 26.
    Conery A, Cao Y, Thompson E, et al. Akt interacts directly with Smad3 to regulate the sensitivity to TGF-beta induced apoptosis. Nat Cell Biol 2004;6:366–372PubMedCrossRefGoogle Scholar
  27. 27.
    Gardai S, Hildeman D, Frankel S, et al. Phosphorylation of Bax Ser 184 by Akt regulates its activity and apoptosis in neutrophils. J Biol Chem 2004;279:21085–21095PubMedCrossRefGoogle Scholar
  28. 28.
    Tanaka Y, Gavrielides M, Mitsuuchi Y, et al. Protein kinase C promotes apoptosis in LNCaP prostate cancer cells through activation of p38 MAPK and inhibition of the Akt survival pathway. J Biol Chem 2003;278:33753–33762PubMedCrossRefGoogle Scholar
  29. 29.
    Haga S, Ogawa W, Todo S, et al. Compensatory recovery of liver mass by Akt-mediated hepatocellular hypertrophy in liver-specific STAT3-deficient mice. J Hepatol 2005;43:799–807PubMedCrossRefGoogle Scholar
  30. 30.
    Chen B, Pan H, Zhu L, et al. Progesterone inhibits the estrogen-induced phosphoinositide 3-kinase→AKT→GSK3β→cyclin D1→pRB pathway to block uterine epithelial cell proliferation. Mol Endocrinol 2005;19(8):1978–1990PubMedCrossRefGoogle Scholar
  31. 31.
    Faridi J, Fawcett J, Wang L, et al. Akt promotes increased mammalian cell size by stimulating protein synthesis and inhibiting protein degradation. Am J Physiol Endocrinol Metab 2003;285:E964–E972PubMedGoogle Scholar
  32. 32.
    Braet F, Shleper M, Paizi M, et al. Liver sinusoidal endothelial cell modulation upon resection and shear stress in vitro. Comp Hepatol 2004;3:7PubMedCrossRefGoogle Scholar
  33. 33.
    Wack KE, Ross MA, Zegarra V, et al. Sinusoidal ultrastructure evaluated during the revascularization of regenerating rat liver. Hepatology 2001;33:363–378PubMedCrossRefGoogle Scholar
  34. 34.
    Nakamura M, Shibasaki M, Nitta Y, et al. Translocation of platelets into Disse space and their entry into hepatocytes in response to lipopolysaccharides, interleukin-1 and tumour necrosis factor: the role of Kupffer cells. J Hepatol 1998;28:991–999PubMedCrossRefGoogle Scholar
  35. 35.
    Endo Y, Nakamura M. The effect of lipopolysaccharide, interleukin-1 and tumour necrosis factor on the hepatic accumulation of 5-hydroxytryptamine and platelets in the mouse. Br J Pharmacol 1992;105:613–619PubMedGoogle Scholar
  36. 36.
    Ohtaki Y, Shimauchi H, Yokochi T, et al. In vivo platelet response to lipopolysaccharide in mice: proposed method for evaluating new antiplatelet drugs. Thromb Res 2003;108:303–309CrossRefGoogle Scholar
  37. 37.
    Klintman D, Li X, Thorlacius H. Important role of P-selection for leukocyte recruitment, hepatocellular injury, and apoptosis in endotoxemic mice. Clin Diagn Lab Immunol 2004;11:56–62PubMedCrossRefGoogle Scholar
  38. 38.
    Peck-Radosavlijevic M, Wichlas M, Zacherl J, et al. Thrombopoietin induces rapid resolution of thrombocytopenia after orthotopic liver transplantation through increased platelet production. Blood 2000;95:795–801Google Scholar
  39. 39.
    Cardier JE, Dempsey J. Thrombopoietin and its receptor, c-mpl, are constitutively expressed by mouse liver endothelial cells: evidence of thrombopoietin as a growth factor for liver endothelial Cells. Blood 1998;91:923–929PubMedGoogle Scholar

Copyright information

© Société Internationale de Chirurgie 2007

Authors and Affiliations

  • Soichiro Murata
    • 1
  • Nobuhiro Ohkohchi
    • 1
  • Ryota Matsuo
    • 1
  • Osamu Ikeda
    • 1
  • Andriy Myronovych
    • 1
  • Reiko Hoshi
    • 1
  1. 1.Department of Surgery, Advanced Biomedical ApplicationsGraduate School of Comprehensive Human Sciences, University of TsukubaTsukubaJapan

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