#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Experimental promotion of liver regeneration after portal vein branch ligation


Authors: V. Liška 1,3;  V. Třeška 1,3;  H. Mírka 2,3;  O. Vyčítal 1,3;  J. Brůha 1,3;  L. Haidingerová 3;  J. Beneš 3,4;  Z. Tonar 3,5;  R. Pálek 1,3;  J. Rosendorf 1,3
Authors‘ workplace: Chirurgická klinika, Univerzita Karlova, Lékařské fakulta v Plzni, Fakultní nemocnice Plzeň 1;  Klinika zobrazovacích metod, Lékařská fakulta v Plzni, Univerzita Karlova 2;  Biomedicínské centrum, Lékařská fakulta v Plzni, Univerzita Karlova 3;  Klinika anestezie, resuscitace a intenzivní medicíny, Lékařská fakulta v Plzni, Univerzita Karlova 4;  Ústav histologie a embryologie, Lékařská fakulta v Plzni, Univerzita Karlova 5
Published in: Rozhl. Chir., 2018, roč. 97, č. 5, s. 239-245.
Category: Original articles

Overview

Introduction:
Portal vein embolization or ligation (PVE/PVL) is part of most multi-stage liver procedures in the case of low future liver remnant volume (FLRV). PVE initiates compensatory hypertrophy of non-occluded liver parenchyma. This hypertrophy is stimulated by an increased volume of portal blood in the non-occluded veins. PVE results in adequate FLRV growth necessary for resection only in 63-96% patients. The aim of this publication is to summarize the possibilities of influencing liver regeneration after PVE/PVL in an experiment using cytokines (TNF-α, IL-6), a monoclonal antibody against TGF-β1 (MAB TGF-β1) and mesenchymal stem cells (MSC).

Methods:
The experimental model of PVE/PVL was chosen as best compatible for potential use in human medicine. 9 (control group), 9 (TNF-α group), 8 (IL-6 group), 6 (MSC group) and 7 piglets (MAB TGF-β1 group) were enrolled in individual studies. We performed laparotomy with PVL of the right-sided liver lobes under general anaesthesia. The following amounts of substances were applied in the non-occluded portal vein branches immediately after PVL: physiological solution (control group), recombinant porcine TNF-α (5 μg/kg), recombinant porcine IL-6 (0.5 μg/kg) and MSC (8.75, 14.0, 17.0, 17.5, 43.0 and 61.0 x 106 MSC). MAB TGF-β1 was applied 24 hours after PVL (40 μg/kg). Biochemical parameters were analysed repeatedly and FLRV ultrasound assessments were performed in the postoperative period. The experiments were ended on postoperative day 14 by sacryfiing the animals under general anaesthesia. Liver samples of hypertrophic and atrophic liver parenchyma were analysed.

Results:
Repeated ultrasound assessments of the effects of MSC, TNF-α, IL-6 and MAB TGF-β1 compared with the physiological solution in the control group demonstrated statistically significant acceleration of FLRV growth in the experimental groups. For MSC, maximum growth was observed between postoperative days 3 and 7, on day 7 for TNF-α, between days 3 and 7 for MAB TGF-β1 and on day 7 for IL-6. Serum levels of AST and ALT increased after PVL and MSC whereas other biochemical parameters showed no statistically significant differences. We identified individual MSC using immunohistochemistry in the hypertrophic tissue of the MSC group. A statistically significant difference was observed in the number of binucleated hepatocytes, with their increased concentration in the IL-6 group.

Conclusion:
Application of IL-6, TNF-α, MAB TGF-β1 and MSC seems to provide suitable stimulation for achieving faster FLRV growth. Nevertheless, many controversial questions still remain to be answered with respect to the mechanism of their respective effects.

Key words:
liver regeneration − portal vein embolization − large animal experiment − mesenchymal stem cells − cytokines


Sources

1. Abdalla EK, Hicks ME, Vauthey JN. Portal vein embolization: rationale, technique and future prospects. British Journal of Surgery 2001;88:165–75.

2. Makuuchi M, Takayasu K, Takayama T. Preoperative transcatheter embolization of portal venous branch for patient receiving extended lobectomy due to the bile duct carcinoma. Journal of Japanese Society for Clinical Surgery 1984;45:14−20.

3. Makuuchi M, Thai BL, Takayasu K, et al. Preoperative portal embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: a preliminary report. Surgery 1990; 107: 521−7.

4. Harada H, Imamura H, Miyagawa S, et al. Fate of human liver after hemihepatic portal vein embolization: cell kinetic and morphometric study. Hepatology 1997;26:1162−70.

5. Kusaka K, Imamura H, Tomiya T, et al. Factors affecting regeneration after portal vein embolization. Hepatogastroenterology 2004;51:532−5.

6. Azoulay D, Castaing D, Smail A, et al. Resection of non-resectable liver metastases from colorectal cancer after percutaneus portal vein embolization. Annals of Surgery 2000;231:480−6.

7. Stefano D, de Baere T, Denys A, et al. Preoperative percutaneus portal vein embolization: evaluation of adverse events in 188 patients. Radiology 2005;234:625−30.

8. Cornell RP. Acute phase responses after acute liver injury by partial hepatectomy in rats as indicators of cytokine release. Hepatology 1990;11:923−31.

9. Fausto N. Liver regeneration. Journal of Hepatology 2000;32:19−31.

10. Fausto N, Riehle KJ. Mechanisms of liver regeneration and their clinical implications. Journal of Hepato-Biliary-Pancreatic Surgery 2005;12:181−9.

11. Michalopoulos GK, DeFrances MC. Liver regeneration. Science 1997;237:60−6.

12. Fukuhara Y, Hirasawa A, Li XK, et al. Gene expression in the regenerating rat liver after partial hepatectomy. Journal of Hepatology 2003;38:784−92.

13. Mangnall D, Bird NC, Majeed AW. The molecular physiology of liver regeneration following partial hepatectomy. Liver International 2003;23:124−38.

14. Zimmermann A. Regulation of liver regeneration. Nephrology Dialysis Transplantation 2004;19:iv6−iv10.

15. Armendariz-Borunda J, Katai H, Jones CM, et al. Transforming growth factor beta gene expression is transiently enhanced at a critical stage during liver regeneration after CCl4 treatment. Laboratory Investigation 1993;69:283−94.

16. Bustos M, Sangro B, Alzuguren P, et al. Liver damage using suicide genes: a model for oval cell activation. The American Journal of Pathology 2000;157:549−59.

17. Kusaka K, Imamura H, Tomiya T, et al. Expression of transforming growth factor-alpha and -beta in hepatic lobes after hemihepatic portal vein embolization. Digestive Diseases and Sciences 2006; 51:1404−12.

18. Oe S, Lemmer ER, Conner EA, et al. Intact signaling by transforming growth factor beta is not required for termination of liver regeneration in mice. Hepatology 2004;40:1098−105.

19. Lilja H, Kamohara Y, Neuman T, et al. Transforming growth factor beta1 helps maintain differentiated functions in mitogen-treated primary rat hepatocyte cultures. Molecular Cell Biology Research Communications 1999;1:188−95.

20. Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology 2008;134: 1655−69.

21. Viebahn CS, Yeoh GC. What fires prometheus? The link between inflammation and regeneration following chronic liver injury. The International Journal of Biochemistry & Cell Biology 2008; 40:855−73.

22. Coelho MC, Tannuri U, Tannuri AC, et al. Expression of interleukin 6 and apoptosis-related genes in suckling and weaning rat model of hepatectomy and liver regeneration. Journal of Pediatric Surgery 2007;45:613−9.

23. Duncan JR, Hicks ME, Cai SR, et al. Embolization of portal vein branches induces hepatocyte replication in swine: a potential step in gene therapy. Radiology 1999;210:467−77.

24. Broering DC, Hillert C, Krupski G, et al. Portal vein embolization vs. portal vein ligation for induction of hypertrophy of the future liver remnant. Journal of Gastrointestinal Surgery 2002;6:905−13.

25. Barry FP. Biology and clinical applications of mesenchymal stem cells. Birth Defects Research Part C: Embryo Today 2003;69:250−6.

26. Jiang Y, Jahagirdar BN, Reinhardt RL, et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002;418:41−9.

27. Lagasse E, Connors H, Al-Dhalimy M, et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nature Medicine 2000;6:1229−34.

28. Petersen BE, Bowen WC, Patrene KD, et al. Bone marrow as a potential source of hepatic oval cells. Science 1999;284:1168−70.

29. Ringe J, Kaps C, Schmitt B, et al. Porcine mesenchymal stem cells. Induction of distinct mesenchymal cell lineages. Cell and Tissue Research 2002;307:321−7.

30. Vassilopoulos G, Wang PR, Russell DW. Transplanted bone marrow regenerates liver by cell fusion. Nature 2003;422:901−4.

31. Wang X, Willenbring H, Akkari Y, et al. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 2003,422:897−901.

32. Aldeguer X, Debonera F, Shaked A, et al. Interleukin-6 from intrahepatic cells of bone marrow origin is required for normal murine liver regeneration. Hepatology 2002;35:40−8.

33. Dahlke MH, Popp FC, Bahlmann FH, et al. Liver regeneration in a retrorsine/CCl4-induced acute liver failure model: do bone marrow-derived cells contribute? Journal of Hepatology 2003;39:365−73.

34. Liska V, Slowik P, Eggenhofer E, et al. Intraportal injection of porcine multipotent mesenchymal stromal cells augments liver regeneration after portal vein embolization. In Vivo 2009;23:229−36.

35. Liska V, Treska V, Mirka H, et al. Tumour necrosis factor-alpha stimulates liver regeneration after partial portal vein ligation – experimental study on porcine model, Hepatogastroenterology 2012;59:114.

36. Liska V, Treska V, Mirka H, et al. Inhibition of transforming growth factor beta-1 augments liver regeneration after partial portal vein ligation in a porcine experimental model. Hepatogastroenterology 2012;59:235−40.

37. Liska V, Treska V, Mirka H, et al. Interleukin-6 augments activation of liver regeneration in porcine model of partial portal vein ligation. Anticancer Research 2009;29:2371−7.

38. Liska V, Treska V, Skalicky T, et al. Cytokines and liver regeneration after partial portal vein ligation in porcine experimental model. Bratislavske lekarske listy 2009;110:447−53.

39. Teoh N, Field J, Farrell G. Interleukin-6 is a key mediator of the hepatoprotective and pro-proliferative effects of ischaemic preconditioning in mice. Journal of Hepatology 2006;45:20−7.

40. Deneme MA, Ok E, Akcan A, et al. Single dose of anti-transforming growth factor-beta1 monoclonal antibody enhances liver regeneration after partial hepatectomy in biliary-obstructed rats. The Journal of Surgical Research 2006;136:280−7.

41. Kang XQ, Zang WJ, Song TS, et al. Rat bone marrow mesenchymal stem cells differentiate into hepatocytes in vitro. World Journal of Gastroenterology 2005;11:3479−84.

42. di Bonzo LV, Ferrero I, Cravanzola C, et al. Human mesenchymal stem cells as a two-edged sword in hepatic regenerative medicine: engraftment and hepatocyte differentiation versus profibrogenic potential. Gut 2008;57:223−31.

43. Dahlke MH, Popp FC, Larsen S, et al. Stem cell therapy of the liver--fusion or fiction? Liver transplantation 2004;10:471−9.

44. Lysy PA, Campard D, Smets F, et al. Persistence of a chimerical phenotype after hepatocyte differentiation of human bone marrow mesenchymal stem cells. Cell Proliferation 2008;41:36−58.

45. Popp FC, Piso P, Schlitt HJ, et al. Therapeutic potential of bone marrow stem cells for liver diseases. Current Stem Cell Research & Therapy 2006;1:411−8.

46. Najimi M, Khuu DN, Lysy PA, et al. Adult-derived human liver mesenchymal-like cells as a potential progenitor reservoir of hepatocytes? Cell Transplantation 2007;16:717−28.

47. Ong SY, Dai H, Leong KW. Hepatic differentiation potential of commercially available human mesenchymal stem cells. Tissue Engineering 2006;12:3477−85.

48. Chamberlain J, Yamagami T, Colletti E, et al. Efficient generation of human hepatocytes by the intrahepatic delivery of clonal human mesenchymal stem cells in fetal sheep. Hepatology 2007;46:1935–45.

49. Banas A, Teratani T, Yamamoto Y, et al. Adipose tissue-derived mesenchymal stem cells as a source of human hepatocytes. Hepatology 2007;46:219−28.

50. Yamamoto Y, Banas A, Murata S, et al. A comparative analysis of the transcriptome and signal pathways in hepatic differentiation of human adipose mesenchymal stem cells. Federation of European Biochemical Societies Journal 2008;275:1260−73.

51. Heinrich S, Jochum W, Graf R, et al. Portal vein ligation and partial hepatectomy differentially influence growth of intrahepatic metastasis and liver regeneration in mice. Journal of Hepatology 2006;45:35−42.

52. Teoh N, Field J, Farrell G. Interleukin-6 is a key mediator of the hepatoprotective and pro-proliferative effects of ischaemic preconditioning in mice. Journal of Hepatology 2006;45:20−7.

53. Baier PK, Baumgartner U, Wolff-Vorbeck G, et al. Hepatocyte proliferation and apoptosis in rat liver after liver injury. Hepato-Gastroenterology 2006;53:747−52.

54. Armendariz-Borunda J, LeGros L Jr, Campollo O, et al. Antisense S-oligodeoxynucleotides down-regulate TGFbeta-production by Kupffer cells from CCl4-injured rat livers. Biochimica et Biophysica Acta 1997; 1353:241−52.

55. Deneme MA, Ok E, Akcan A, et al. Single dose of anti-transforming growth factor-beta1 monoclonal antibody enhances liver regeneration after partial hepatectomy in biliary-obstructed rats. The Journal of Surgical Research 2006;136:280−7.

56. Delgado-Rizo V, Salazar A, Panduro A, et al. Treatment with anti-transforming growth factor beta antibodies influences an altered pattern of cytokines gene expression in injured rat liver. Biochimica et Biophysica Acta 1998;1442:20−7.

Labels
Anaesthesiology, Resuscitation and Inten Paediatric surgery Paediatric urologist Vascular surgery Chest surgery Maxillofacial surgery Plastic surgery Surgery Intensive Care Medicine Cardiac surgery Cardiology Neurosurgery Clinical oncology Orthopaedics Burns medicine Orthopaedic prosthetics Rehabilitation Nurse Traumatology Trauma surgery Urology Medical student
Topics Journals
Login
Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.

Login

Don‘t have an account?  Create new account

#ADS_BOTTOM_SCRIPTS#