Regulation of hepatocyte proliferation after subtotal liver resection in rats

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Abstract

Hepatocyte proliferation is the main cellular mechanism of liver regeneration. However, after removal of more than 80 % of the liver mass, a temporary block of hepatocyte proliferation is observed, which may be the cause of impaired regeneration during transplantation and liver resection in the clinical practice. The current study aims to analyze the molecular mechanisms of hepatocyte proliferation impairment after subtotal liver resection in rats. In male Wistar rats, a model of liver regeneration after subtotal resection is reproduced - removal of more than 80 % of liver mass. Using the methods of immunohistochemistry, PCR-RT, western blot, possible molecular mechanisms of slowing down the proliferation of hepatocytes were studied. It was found that expression of cyclin D1 and E increased only 30 hours after surgery. Their appearance coincides with the beginning of transcription of genes for Cyclins D1 and E1 at 30 h after surgery. The corresponding increase in concentrations of cyclin D, and E proteins is further delayed till 48 h after surgery. These results indicate that, in this particular model, hepatocytes are reluctant to undergo transition between G0- and G1 -phases of cell cycle. We have observed a prolonged decrease in the expression of protooncogene C-met (the hepatocyte growth factor receptor-encoding gene Met). We have also observed an increase in expression of the transforming growth factor beta-1 receptor-encoding gene TgfbrII. At the same time, irreversible block of hepatocyte proliferation was prevented by expression of certain factors, notably of the TWEAK/ Fn14 signaling pathway: concentrations of the corresponding proteins in remnant livers have peaked from 24 h to 48 h after surgery. Thus, after subtotal liver resection, the remaining hepatocytes are exposed to a large scope of both mitogenic and antimitogenic factors. Proliferative behavior of hepatocytes in remnant livers is determined by fine balance of these factors. The prevalence of antimitogenic factors in the early period after surgery delays the onset of hepatocyte proliferation.

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About the authors

A. V Elchaninov

V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology; Peoples' Friendship University of Russia

A. V Makarov

N.I. Pirogov Russian National Research Medical University

I. G Vorobieva

V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

E. Y Kananykhina

Scientific Research Institute of Human Morphology

A. V Lokhonina

V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology; Peoples' Friendship University of Russia

G. B Bolshakova

Scientific Research Institute of Human Morphology

V. V Glinkina

N.I. Pirogov Russian National Research Medical University

D. V Goldshtein

Research Centre of Medical Genetics

T. Kh Fatkhudinov

V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology; Peoples' Friendship University of Russia

Email: fatkhudinov@gmail.com

References

  1. Stanger B.Z. Cellular homeostasis and repair in the mammalian liver. Annu. Rev. Physiol. 2015; 77: 179-200.
  2. Malato Y., Naqvi S., Schürmann N. et al. Fate tracing of mature hepatocytes in mouse liver homeostasis and regeneration. J. Clin. Investig. 2011; 121: 1850-60.
  3. Yanger K., Knigin D., Zong Y. et al. Adult hepatocytes are generated by self-duplication rather than stem cell differentiation. Cell Stem Cell 2014; 15(3): 340-9.
  4. Michalopoulos G.K. Advances in liver regeneration. Expert Rev. Gastroenterol. Hepatol. 2014; 8(8): 897-907.
  5. Cressman D.E., Greenbaum L.E., DeAngelis R.A. et al. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science 1996; 274(5291): 1379-83.
  6. Sanchez A., Fabregat I. Growth factor- and cytokine-driven pathways governing liver stemness and differentiation. World J. Gastroenterol. 2010; 16(41): 5148-61.
  7. Paranjpe S., Bowen W.C., Bell A.W. et al. Cell cycle effects resulting from inhibition of hepatocyte growth factor and its receptor c-Met in regenerating rat livers by RNA interference. Hepatology 2007; 45(6):1471-7
  8. Song Z., Humar B., Gupta A. et al. Exogenous melatonin protects small-for-size liver grafts by promoting monocyte infiltration and releases interleukin-6. J. Pineal Res. 2018; 65(1): e12486.
  9. Ельчанинов А.В., Фатхудинов Т.Х., Кананыхина Е.Ю. и др. Экспрессия генов цитокинов и факторов роста в печени после субтотальной резекции у крыс. Гены и клетки 2016; 11(1): 61-7.
  10. Elchaninov A., Fatkhudinov T., Usman N. et al. Molecular survey of cell source usage during subtotal hepatectomy-induced liver regeneration in rats. PLoS One 2016; 11(9): e0162613.
  11. Elchaninov A.V., Fatkhudinov T.K., Usman N.Y. et al. Dynamics of macrophage populations of the liver after subtotal hepatectomy in rats. BMC Immunol. 2018; 19(1): 23.
  12. Романова Л.К. Регуляция восстановительных процессов. Москва: Издательство МГУ; 1984.
  13. Darzynkiewicz Z., Zhao H., Zhang S. et al. Initiation and termination of DNA replication during S phase in relation to cyclins D1, E and A, p21WAF1, Cdt1 and the p12 subunit of DNA polymerase 8 revealed in individual cells by cytometry. Oncotarget 2015; 6(14): 11735-50.
  14. Böhmer R.M., Scharf E., Assoian R.K. Cytoskeletal integrity is required throughout the mitogen stimulation phase of the cell cycle and mediates the anchorage-dependent expression of cyclin D1. Mol. Biol. Cell 1996; 7(1): 101-11.
  15. Huh C.G., Factor V.M., Sanchez A. et al. Hepatocyte growth factor/ c-met signaling pathway is required for efficient liver regeneration and repair. PNAS USA 2004; 101(13): 4477-82.
  16. Karkampouna S., Ten Dijke P., Dooley S. et al. TGFß signaling in liver regeneration. Curr. Pharm. Des. 2012; 18(27): 4103-13.
  17. Romero-Gallo J., Sozmen E.G., Chytil A. et al. Inactivation of TGF-beta signaling in hepatocytes results in an increased proliferative response after partial hepatectomy. Oncogene 2005; 24(18): 3028-41.
  18. Grasl-Kraupp B., Rossmanith W., Ruttkay-Nedecky B. et al. Levels of transforming growth factor beta and transforming growth factor beta receptors in rat liver during growth, regression by apoptosis and neoplasia. Hepatology 1998; 28(3): 717-26.
  19. Pediaditakis P., Lopez-Talavera J.C., Petersen B. et al. The processing and utilization of hepatocyte growth factor/scatter factor following partial hepatectomy in the rat. Hepatology 2001; 34(4 Pt 1): 688-93.
  20. Lehmann K., Tschuor C., Rickenbacher A. et al. Liver failure after extended hepatectomy in mice is mediated by a p21-dependent barrier to liver regeneration. Gastroenterology 2012; 143(6): 1609-19.e4.
  21. Karaca G., Swiderska-Syn M., Xie G. et al. TWEAK/Fn14 signaling is required for liver regeneration after partial hepatectomy in mice. PLoS One 2014; 9(1): e83987.
  22. Burkly L.C. TWEAK/Fn14 axis: the current paradigm of tissue injury-inducible function in the midst of complexities. Semin. Immunol. 2014; 26(3): 229-36.
  23. Burkly L.C., Michaelson J.S., Zheng T.S. TWEAK/Fn14 pathway: an immunological switch for shaping tissue responses. Immunol. Rev. 2011; 244(1): 99-114.
  24. Elchaninov A.V., Fatkhudinov T.K., Arutyunyan I.V. et al. Dynamics of Expression of Cytokine Genes and Macrophage Content in the Lungs and Kidneys after Subtotal Hepatectomy in Rats. Bull. Exp. Biol. Med. 2018; 165(1): 136-41.
  25. Kono S., Nagaike M., Matsumoto K. et al. Marked induction of hepatocyte growth factor mRNA in intact kidney and spleen in response to injury of distant organs. Biochem. Biophys. Res. Commun. 1992; 186(2): 991-8.
  26. Yanagita K., Nagaike M., Ishibashi H. Lung may have an endocrine function producing hepatocyte growth factor in response to injury of distal organs. Biochem. Biophys. Res. Commun. 1992; 182(2): 802-9.
  27. Elchaninov A.V., Fatkhudinov T.Kh., Kananykhina E.Y. et al. Role of Progenitor Cells in Liver Regeneration after Subtotal Resection. Bull. Exp. Biol. Med. 2016; 161(1): 155-61.
  28. Lefebvre V., Dumitriu B., Penzo-Méndez A. et al. Control of cell fate and differentiation by Sry-related high-mobility-group box (Sox) transcription factors. Int. J. Biochem. Cell Biol. 2007; 39(12): 2195-214.
  29. Wang X., Ju Y., Zhou M.I. et al. Upregulation of SOX9 promotes cell proliferation, migration and invasion in lung adenocarcinoma. Oncol. Lett. 2015; 10(2): 990-4.
  30. Winkles J.A. The TWEAK-Fn14 cytokine-receptor axis: discovery, biology and therapeutic targeting. Nat. Rev. Drug Discov. 2008; 7(5): 411-25.

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