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Pre-stimulated Mice with Carbon Tetrachloride Accelerate Early Liver Regeneration After Partial Hepatectomy

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Abstract

Background and Aim

The liver has a high capacity of its regeneration. Most hepatic cells are quiescent unless otherwise stimulated such as their injury or ablation. A previous study suggest that pre-activated hepatic cells have a positive effect on their regeneration. In this study, we examined whether the pre-activated hepatic cells for regeneration accelerate the subsequent liver regeneration.

Methods

We administered a single injection of carbon tetrachloride (CCl4) to mice 7 days before partial hepatectomy (PHx). Liver weight/body weight ratio and several parameters for cell proliferation such as mitotic index and the number of Ki67 positive cells in the liver were examined after PHx as indexes of liver regeneration.

Results

Compared to control mice, those pre-stimulated with CCl4 showed earlier liver regeneration 48 h after PHx. Regardless of their accelerated regeneration, pre-stimulated mice showed less cell proliferation than did control mice during liver regeneration. Hepatic fibrosis was not observed in both control and CCl4-pretreated mice after PHx. Mice pre-treated with CCl4 showed the higher matrix metalloproteinase 9 (MMP9) expression than those pre-treated with olive oil. When matrix metalloproteinase 9 (MMP9) activity was inhibited, the pre-stimulated mice did not demonstrate accelerated liver regeneration and they returned to the original state for cell proliferations after PHx.

Conclusions

Pre-activated liver by CCl4 promoted its subsequent regeneration after PHx. This was not a cause of fibrosis and partly dependent on MMP9 pre-activity rather than cell proliferation in liver. Our findings would not only provide a novel strategy for liver regeneration without cell proliferation as much as possible and also propose a new method for liver transplantation.

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References

  1. Palmes D, Spiegel HU. Animal models of liver regeneration. Biomaterials. 2004;25:1601–1611.

    Article  CAS  PubMed  Google Scholar 

  2. Michalopoulos GK, DeFrances M. Liver regeneration. Adv Biochem Eng Biotechnol. 2005;93:101–134.

    CAS  PubMed  Google Scholar 

  3. Michalopoulos GK. Liver regeneration. J Cell Physiol. 2007;213:286–300.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Fausto N, Campbell JS, Riehle KJ. Liver regeneration. Hepatology. 2006;43:S45–S53.

    Article  CAS  PubMed  Google Scholar 

  5. Menjo M, Ikeda K, Nakanishi M. Regulation of g1 cyclin-dependent kinases in liver regeneration. J Gastroenterol Hepatol. 1998;13:S100–S105.

    CAS  PubMed  Google Scholar 

  6. Fausto N, Campbell JS, Riehle KJ. Liver regeneration. J Hepatol. 2012;57:692–694.

    Article  PubMed  Google Scholar 

  7. Haruyama T, Ajioka I, Akaike T, Watanabe Y. Regulation and significance of hepatocyte-derived matrix metalloproteinases in liver remodeling. Biochem Biophys Res Commun. 2000;272:681–686.

    Article  CAS  PubMed  Google Scholar 

  8. Jacob S, Sudhakaran PR. Changes in the activity of matrix metalloproteinases in regenerating rat liver after ccl4-induced injury. Indian J Biochem Biophys. 2003;40:324–329.

    CAS  PubMed  Google Scholar 

  9. Wu Q, Gong D, Tian N, et al. Protection of regenerating liver after partial hepatectomy from carbon tetrachloride hepatotoxicity in rats: roles of mitochondrial uncoupling protein 2 and atp stores. Dig Dis Sci. 2009;54:1918–1925.

    Article  CAS  PubMed  Google Scholar 

  10. Nejak-Bowen K, Orr A, Bowen WC Jr, Michalopoulos GK. Conditional genetic elimination of hepatocyte growth factor in mice compromises liver regeneration after partial hepatectomy. PLoS One. 2013;8:e59836.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Ito H, Ando K, Nakayama T, et al. Role of valpha 14 nkt cells in the development of impaired liver regeneration in vivo. Hepatology. 2003;38:1116–1124.

    Article  CAS  PubMed  Google Scholar 

  12. Jiao J, Sastre D, Fiel MI, et al. Dendritic cell regulation of carbon tetrachloride-induced murine liver fibrosis regression. Hepatology. 2012;55:244–255.

    Article  PubMed Central  PubMed  Google Scholar 

  13. Darzynkiewicz Z, Gong J, Juan G, Ardelt B, Traganos F. Cytometry of cyclin proteins. Cytometry. 1996;25:1–13.

    Article  CAS  PubMed  Google Scholar 

  14. Delahunty TJ, Rubinstein D. Accumulation and release of triglycerides by rat liver following partial hepatectomy. J Lipid Res. 1970;11:536–543.

    CAS  PubMed  Google Scholar 

  15. Csanaky IL, Aleksunes LM, Tanaka Y, Klaassen CD. Role of hepatic transporters in prevention of bile acid toxicity after partial hepatectomy in mice. Am J Physiol Gastrointest Liver Physiol. 2009;297:G419–G433.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Koh SL, Ager E, Malcontenti-Wilson C, Muralidharan V, Christophi C. Blockade of the renin-angiotensin system improves the early stages of liver regeneration and liver function. J Surg Res. 2013;179:66–71.

    Article  CAS  PubMed  Google Scholar 

  17. Hu J, Srivastava K, Wieland M, et al. Endothelial cell-derived angiopoietin-2 controls liver regeneration as a spatiotemporal rheostat. Science. 2014;343:416–419.

    Article  CAS  PubMed  Google Scholar 

  18. Miyaoka Y, Ebato K, Kato H, Arakawa S, Shimizu S, Miyajima A. Hypertrophy and unconventional cell division of hepatocytes underlie liver regeneration. Curr Biol. 2012;22:1166–1175.

    Article  CAS  PubMed  Google Scholar 

  19. Shi JH, Scholz H, Huitfeldt HS, Line PD. The effect of hepatic progenitor cells on experimental hepatocellular carcinoma in the regenerating liver. Scand J Gastroenterol. 2014;49:99–108.

    Article  CAS  PubMed  Google Scholar 

  20. Koh SL, Ager EI, Christophi C. Liver regeneration and tumour stimulation: implications of the renin-angiotensin system. Liver Int. 2010;30:1414–1426.

    Article  CAS  PubMed  Google Scholar 

  21. Gazit V, Huang J, Weymann A, Rudnick DA. Analysis of the role of hepatic PPARγ expression during mouse liver regeneration. Hepatology. 2012;56:1489–1498.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Wang C, Pattabiraman N, Zhou JN, et al. Cyclin d1 repression of peroxisome proliferator-activated receptor gamma expression and transactivation. Mol Cell Biol. 2003;23:6159–6173.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Mehendale HM. Tissue repair: an important determinant of final outcome of toxicant-induced injury. Toxicol Pathol. 2005;33:41–51.

    Article  CAS  PubMed  Google Scholar 

  24. Ding BS, Cao Z, Lis R, et al. Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature. 2014;505:97–102.

    Article  PubMed Central  PubMed  Google Scholar 

  25. Kato H, Kuriyama N, Duarte S, Clavien PA, Busuttil RW, Coito AJ. Mmp-9 deficiency shelters endothelial pecam-1 expression and enhances regeneration of steatotic livers after ischemia and reperfusion injury. J Hepatol. 2014;60:1032–1039.

  26. Olle EW, Ren X, McClintock SD, et al. Matrix metalloproteinase-9 is an important factor in hepatic regeneration after partial hepatectomy in mice. Hepatology. 2006;44:540–549.

    Article  CAS  PubMed  Google Scholar 

  27. Hamada T, Fondevila C, Busuttil RW, Coito AJ. Metalloproteinase-9 deficiency protects against hepatic ischemia/reperfusion injury. Hepatology. 2008;47:186–198.

    Article  CAS  PubMed  Google Scholar 

  28. Moore C, Shen XD, Gao F, Busuttil RW, Coito AJ. Fibronectin-alpha4beta1 integrin interactions regulate metalloproteinase-9 expression in steatotic liver ischemia and reperfusion injury. Am J Pathol. 2007;170:567–577.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Iwasaki H, Arai F, Kubota Y, Dahl M, Suda T. Endothelial protein c receptor-expressing hematopoietic stem cells reside in the perisinusoidal niche in fetal liver. Blood. 2010;116:544–553.

    Article  CAS  PubMed  Google Scholar 

  30. Quondamatteo F, Knittel T, Mehde M, Ramadori G, Herken R. Matrix metalloproteinases in early human liver development. Histochem Cell Biol. 1999;112:277–282.

    Article  CAS  PubMed  Google Scholar 

  31. Feng M, Wang H, Wang Q, Guan W. Matrix metalloprotease 9 promotes liver recovery from ischemia and reperfusion injury. J Surg Res. 2013;180:156–161.

    Article  CAS  PubMed  Google Scholar 

  32. Ji J. Dual role of matrix metalloprotease 9 in liver ischemia and reperfusion injury. J Surg Res. 2013;185:545–546.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by Grant-in-Aid for Research Activity start-up (25893084) from the Ministry for Education, Culture, Sports, Science and Technology of Japan. We are grateful to Kyoko Takahashi for technical assistance.

Conflict of interest

None.

Author information

Author notes

  1. Yuko Arioka

    Present address: Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan

Authors and Affiliations

  1. Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan

    Yuko Arioka, Hiroyasu Ito, Tatsuya Ando, Hideyuki Ogiso & Mitsuru Seishima

  2. Division of Animal Experiment, Life Science Research Center, Gifu University, 1-1 Yanagido, Gifu, 501-1194, Japan

    Akihiro Hirata

  3. Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan

    Akira Hara

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  1. Yuko Arioka
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Corresponding author

Correspondence to Yuko Arioka.

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10620_2015_3536_MOESM1_ESM.tif

Supplementary Fig. 1 The relative mRNA level of Mmp8 (A) and Mmp13 (B) following CCl4 administration. n = 4 for cont, 24 h and day 7. n = 3 for day 3. The relative mRNA level of Mmp8 (C) and Mmp13 (D) after PHx. Values are normalized to Actb. n = 4–6 for each group in both olive oil- and CCl4-treated mice. *p < 0.05

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Arioka, Y., Ito, H., Ando, T. et al. Pre-stimulated Mice with Carbon Tetrachloride Accelerate Early Liver Regeneration After Partial Hepatectomy. Dig Dis Sci 60, 1699–1706 (2015). https://doi.org/10.1007/s10620-015-3536-9

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  • DOI: https://doi.org/10.1007/s10620-015-3536-9

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