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Liver Repair and Regeneration in Transplant: State of the Art

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Abstract

Purpose of Review

The liver is known for having the unusual capacity to regenerate itself following injury. Transplantation is necessarily associated with injury, cell death, and regeneration. The regenerative capacity of the liver is vital to the optimal outcomes of patients who undergo transplant.

Recent Findings

In this review, we will investigate the mechanisms, including cells and some of the major molecules and cytokines in this process. These will help to elucidate the importance of these molecules while at the same time demonstrating the complexity of this process. Finally, external factors which affect optimal regeneration of the liver will be discussed.

Summary

Several factors affect liver regeneration such as ischemic reperfusion injury, graft size, immunosuppression, donor age, steatosis, nutrition, and viral hepatitis. The conglomeration and consolidation of all this information is meant to provide the reader with a deeper picture of this process, while also serving to lay a foundation for ideas for further research in this field and consequently improve transplant outcomes.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.

    Taub R. Liver regeneration: from myth to mechanism. Nat Rev Mol Cell Biol. 2004;5(10):836.

  2. 2.

    Michalopoulos GK, DeFrances MC. Liver regeneration. Science. 1997;276(5309):60–6.

  3. 3.

    Sell S. Heterogeneity and plasticity of hepatocyte lineage cells. Hepatology. 2001;33(3):738–50.

  4. 4.

    • Sable SA, Maheshwari S, Sharma S, Yadav K, Chauhan A, Kapoor S, et al. Kinetics of liver regeneration in donors after living donor liver transplantation: A retrospective analysis of “2/3rd partial hepatectomy” model at 3 months. Indian J Gastroenterol. 2018;37(2):133–40 This source discusses the 2/3 partial hepatectomy in mice, which is a common method to study liver regeneration and is referenced at several points throughout the paper.

  5. 5.

    Kurokawa T, Ohkohchi N. Platelets in liver disease, cancer and regeneration. World J Gastroenterol. 2017 May 14;23(18):3228–39.

  6. 6.

    •• Lisman T, Luyendyk JP. Platelets as modulators of liver diseases. In Seminars in thrombosis and hemostasis 2018 (Vol. 44, No. 02, pp. 114–125). Thieme Medical Publishers. Provides an overview of the role of platelets in liver regeneration, which is the main focus of the first section of this review. Discusses mechanisms and clinical relevance.

  7. 7.

    Li L, Wang H, Yang J, Jiang L, Yang J, Wang W, et al. Immediate postoperative low platelet counts after living donor liver transplantation predict early allograft dysfunction. Medicine. 2015;94(34):1–7.

  8. 8.

    Maan R, de Knegt RJ, Veldt BJ. Management of thrombocytopenia in chronic liver disease: focus on pharmacotherapeutic strategies. Drugs. 2015;75(17):1981–92.

  9. 9.

    Han S, Ko JS, Gwak MS, Kim GS. Association of platelet count and platelet transfusion with serotonin level during living donor liver transplantation: possible connection to graft regeneration. In Transplantation proceedings 2018 (Vol. 50, No. 4, pp. 1104–1107). Elsevier.

  10. 10.

    Matsuo R, Ohkohchi N, Murata S, Ikeda O, Nakano Y, Watanabe M, et al. Platelets strongly induce hepatocyte proliferation with IGF-1 and HGF in vitro. J Surg Res. 2008;145(2):279–86.

  11. 11.

    Lesurtel M, Clavien PA. Platelet-derived serotonin: translational implications for liver regeneration. Hepatology. 2014;60(1):30–3.

  12. 12.

    Balasubramanian S, Paulose CS. Induction of DNA synthesis in primary cultures of rat hepatocytes by serotonin: possible involvement of serotonin S2 receptor. Hepatology. 1998;27(1):62–6.

  13. 13.

    Starlinger P, Haegele S, Offensperger F, Oehlberger L, Pereyra D, Kral JB, et al. The profile of platelet α-granule released molecules affects postoperative liver regeneration. Hepatology. 2016;63(5):1675–88.

  14. 14.

    Massagué J, Blain SW, Lo RS. TGFβ signaling in growth control, cancer, and heritable disorders. Cell. 2000;103(2):295–309.

  15. 15.

    Shi Y, Massagué J. Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell. 2003;113(6):685–700.

  16. 16.

    Romero-Gallo J, Sozmen EG, Chytil A, Russell WE, Whitehead R, Parks WT, et al. Inactivation of TGF-β signaling in hepatocytes results in an increased proliferative response after partial hepatectomy. Oncogene. 2005;24(18):3028–41.

  17. 17.

    • Rao S, Zaidi S, Banerjee J, Jogunoori W, Sebastian R, Mishra B, et al. Transforming growth factor-β in liver cancer stem cells and regeneration. Hepatol Commun. 2017;1(6):477–93 Provides an overview of the role of TGF-β in liver regeneration. Lays a comprehensive foundation for the current section of the review.

  18. 18.

    Thenappan A, Li Y, Kitisin K, Rashid A, Shetty K, Johnson L, et al. Role of transforming growth factor β signaling and expansion of progenitor cells in regenerating liver. Hepatology. 2010;51(4):1373–82.

  19. 19.

    Niwa H, Miyazaki JI, Smith AG. Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet. 2000;24(4):372–6.

  20. 20.

    Thanan R, Pairojkul C, Pinlaor S, Khuntikeo N, Wongkham C, Sripa B, et al. Inflammation-related DNA damage and expression of CD133 and Oct3/4 in cholangiocarcinoma patients with poor prognosis. Free Radic Biol Med. 2013;65:1464–72.

  21. 21.

    Karkampouna S, Goumans MJ, Ten Dijke P, Dooley S, Kruithof-de JM. Inhibition of TGFβ type I receptor activity facilitates liver regeneration upon acute CCl 4 intoxication in mice. Arch Toxicol. 2016;90(2):347–57.

  22. 22.

    Nishimoto M, Miyagi S, Yamagishi T, Sakaguchi T, Niwa H, Muramatsu M, et al. Oct-3/4 maintains the proliferative embryonic stem cell state via specific binding to a variant octamer sequence in the regulatory region of the UTF1 locus. Mol Cell Biol. 2005;25(12):5084–94.

  23. 23.

    Leibing T, Géraud C, Augustin I, Boutros M, Augustin HG, Okun JG, et al. Angiocrine Wnt signaling controls liver growth and metabolic maturation in mice. Hepatology. 2018;68(2):707–22.

  24. 24.

    Huh CG, Factor VM, Sánchez A, Uchida K, Conner EA, Thorgeirsson SS. Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proc Natl Acad Sci. 2004;101(13):4477–82.

  25. 25.

    Wang Y, Zhu P, Wang J, Zhu X, Luo J, Meng S, et al. Long noncoding RNA lncHand2 promotes liver repopulation via c-Met signaling. J Hepatol. 2018;69(4):861–72.

  26. 26.

    Shaker ME, Ashamallah SA, El-Mesery M. The novel c-Met inhibitor capmatinib mitigates diethylnitrosamine acute liver injury in mice. Toxicol Lett. 2016;261:13–25.

  27. 27.

    Zhong H, Yin H. Role of lipid peroxidation derived 4-hydroxynonenal (4-HNE) in cancer: focusing on mitochondria. Redox Biol. 2015;4:193–9.

  28. 28.

    • Bouattour M, Raymond E, Qin S, Cheng AL, Stammberger U, Locatelli G, et al. Recent developments of c-Met as a therapeutic target in hepatocellular carcinoma. Hepatology. 2018;67(3):1132–49 Discusses new discoveries relating to the c-Met pathway and its role in cancer. The mechanisms behind this pathway can be correlated to c-Met’s role in liver regeneration.

  29. 29.

    Gomez-Quiroz LE, Seo D, Lee YH, Kitade M, Gaiser T, Gillen M, et al. Loss of c-Met signaling sensitizes hepatocytes to lipotoxicity and induces cholestatic liver damage by aggravating oxidative stress. Toxicology. 2016;361:39–48.

  30. 30.

    Schmidt-Arras D, Rose-John S. IL-6 pathway in the liver: from physiopathology to therapy. J Hepatol. 2016;64(6):1403–15.

  31. 31.

    Wolf J, Rose-John S, Garbers C. Interleukin-6 and its receptors: a highly regulated and dynamic system. Cytokine. 2014;70(1):11–20.

  32. 32.

    Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro-and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta. 2011;1813(5):878–88.

  33. 33.

    Interleukin-6 Receptor [Internet]. Sino Biological: Sino Biological Inc.; c2007–19. [cited 16 December 2019]. Available from: https://www.sinobiological.com/interleukin-6-receptor-sinobio.html.

  34. 34.

    Rehman K, Akash MS, Liaqat A, Kamal S, Qadir MI, Rasul A. Role of interleukin-6 in development of insulin resistance and type 2 diabetes mellitus. Crit Rev Eukaryot Gene Expr. 2017;27(3):229–36.

  35. 35.

    Kurauti MA, Costa-Júnior JM, Ferreira SM, Santos GJ, Sponton CH, Carneiro EM, et al. Interleukin-6 increases the expression and activity of insulin-degrading enzyme. Sci Rep. 2017;7:46750.

  36. 36.

    • Lanton T, Shriki A, Nechemia-Arbely Y, Abramovitch R, Levkovitch O, Adar R, et al. Interleukin 6–dependent genomic instability heralds accelerated carcinogenesis following liver regeneration on a background of chronic hepatitis. Hepatology. 2017;65(5):1600–11 Demonstrates a relationship between liver carcinogenesis and partial hepatectomy, specifically in terms of how IL-6 plays a role in each pathway.

  37. 37.

    Smit JJ, Schinkel AH, Elferink RO, Groen AK, Wagenaar E, Van Deemter L, et al. Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Cell. 1993;75(3):451–62.

  38. 38.

    Popov Y, Patsenker E, Fickert P, Trauner M, Schuppan D. Mdr2 (Abcb4)−/−mice spontaneously develop severe biliary fibrosis via massive dysregulation of pro-and antifibrogenic genes. J Hepatol. 2005;43(6):1045–54.

  39. 39.

    Zhang X, Zeng Y, Qu Q, Zhu J, Liu Z, Ning W, et al. PD-L1 induced by IFN-γ from tumor-associated macrophages via the JAK/STAT3 and PI3K/AKT signaling pathways promoted progression of lung cancer. Int J Clin Oncol. 2017;22(6):1026–33.

  40. 40.

    Nakano T, Chen IH, Goto S, Lai CY, Tseng HP, Hsu LW, et al. Hepatic miR-301a as a liver transplant rejection biomarker? And its role for Interleukin-6 production in hepatocytes. OMICS. 2017;21(1):55–66.

  41. 41.

    Romano M, Sironi M, Toniatti C, Polentarutti N, Fruscella P, Ghezzi P, et al. Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity. 1997;6(3):315–25.

  42. 42.

    Perry BC, Soltys D, Toledo AH, Toledo-Pereyra LH. Tumor necrosis factor-α in liver ischemia/reperfusion injury. J Investig Surg. 2011;24(4):178–88.

  43. 43.

    Feingold KR, Barker ME, Jones AL, Grunfeld C. Localization of tumor necrosis factor–stimulated DNA synthesis in the liver. Hepatology. 1991;13(4):773–9.

  44. 44.

    •• Yang B, Luo Q, Kang Q, Wang J, Xiao C, Li ZP, et al. Tumor necrosis factor-α and transforming growth factor-β1 balance liver stem cell differentiation in cholestatic cirrhosis. Nan Fang Yi Ke Da Xue Xue Bao. 2018;38(4):375–83 Provides a thorough discussion of TGF-β and TNF-α and their roles in hepatic stem cell differentiation, as well as outlining a study of these molecules. These two molecules are discussed at multiple points in this review, and are important to the regenerative response as a whole.

  45. 45.

    Sorg UR, Behnke K, Degrandi D, Reich M, Keitel V, Herebian D, et al. Cooperative role of lymphotoxin β receptor and tumor necrosis factor receptor p55 in murine liver regeneration. J Hepatol. 2016;64(5):1108–17.

  46. 46.

    •• Chae MS, Moon KU, Chung HS, Park CS, Lee J, Choi JH, et al. Serum interleukin-6 and tumor necrosis factor-α are associated with early graft regeneration after living donor liver transplantation. PloS One. 2018;13(4):e0195262 This is a study which looks at the relationship between IL-6 and TNF-α levels and graft regeneration. These two molecules are discussed widely throughout this review, and demonstrating their importance is critical.

  47. 47.

    Ji T, Li G, Chen J, Zhao J, Li X, Lin H, et al. Distinct role of interleukin-6 and tumor necrosis factor receptor-1 in oval cell-mediated liver regeneration and inflammation-associated hepatocarcinogenesis. Oncotarget. 2016;7(41):66635–46.

  48. 48.

    • Wang B, Kaufmann B, Engleitner T, Lu M, Mogler C, Olsavszky V, et al. Brg1 promotes liver regeneration after partial hepatectomy via regulation of cell cycle. Sci Rep. 2019;9(1):2320 Describes the mechanism behind the effect of Brg-1 on liver regeneration and the cell cycle.

  49. 49.

    Sinha S, Verma S, Chaturvedi MM. Differential expression of SWI/SNF chromatin remodeler subunits Brahma and Brahma-related gene during drug-induced liver injury and regeneration in mouse model. DNA Cell Biol. 2016;35(8):373–84.

  50. 50.

    • Li N, Kong M, Zeng S, Hao C, Li M, Li L, et al. Brahma related gene 1 (Brg1) contributes to liver regeneration by epigenetically activating the Wnt/β-catenin pathway in mice. FASEB J. 2018;33(1):327–38 Describes another mechanism behind the effects of Brg-1 on liver regeneration.

  51. 51.

    Li M, Chu Z, Tan Z, Jin Y, Xu M, Ji Q. Impact of donor age on liver regeneration and function following adult living donor liver transplantation. Exp Ther Med. 2019;17(5):3965–70.

  52. 52.

    Tanemura A, Mizuno S, Wada H, Yamada T, Nobori T, Isaji S. Donor age affects liver regeneration during early period in the graft liver and late period in the remnant liver after living donor liver transplantation. World J Surg. 2012;36(5):1102–11.

  53. 53.

    Tsukamoto I, Nakata R, Kojo S. Effect of ageing on rat liver regeneration after partial hepatectomy. Biochem Mol Biol Int. 1993;30(4):773–8.

  54. 54.

    Selzner N, Selzner M, Tian Y, Kadry Z, Clavien PA. Cold ischemia decreases liver regeneration after partial liver transplantation in the rat: a TNF-α/IL-6–dependent mechanism. Hepatology. 2002;36(4):812–8.

  55. 55.

    Hua ZY, Song J, Cheng F, Yu Y, Gao Y, Yao A, et al. The effect of hepatocyte growth factor on the initiation phase of liver regeneration after cold ischemia in a rat model of small-for-size liver transplantation. Hepato-gastroenterology. 2012;59(117):1548–52.

  56. 56.

    • Allaire M, Gilgenkrantz H. The impact of steatosis on liver regeneration. Hormone molecular biology and clinical investigation. In: As well as addressing the effect of steatosis on liver regeneration, this source also discusses other several factors that impede the regenerative process; 2018. It also touches upon some therapeutics.

  57. 57.

    Zhang BH, Weltman M, Farrell G. Does steatohepatitis impair liver regeneration? A study in a dietary model of non-alcoholic steatohepatitis in rats. J Gastroenterol Hepatol. 1999;14(2):133–7.

  58. 58.

    • Rajakumar A, Kaliamoorthy I, Rela M, Mandell MS. Small-for-size syndrome: bridging the gap between liver transplantation and graft recovery. In Seminars in cardiothoracic and vascular anesthesia 2017 (Vol. 21, No. 3, pp. 252–261). Sage CA: Los Angeles: SAGE Publications. This is a discussion of small-for-size syndrome, including pathophysiology as well as appropriate management methods.

  59. 59.

    Zhong Z, Schwabe RF, Kai Y, He L, Yang L, Bunzendahl H, et al. Liver regeneration is suppressed in small-for-size liver grafts after transplantation: involvement of c-Jun N-terminal kinase, cyclin D1, and defective energy supply. Transplantation. 2006;82(2):241–50.

  60. 60.

    Ma Y, Lv X, He J, Liu T, Wen S, Wang L. Wnt agonist stimulates liver regeneration after small-for-size liver transplantation in rats. Hepatol Res. 2016;46(3):E154–64.

  61. 61.

    Liu Q, Rehman H, Krishnasamy Y, Haque K, Schnellmann RG, Lemasters JJ, et al. Amphiregulin stimulates liver regeneration after small-for-size mouse liver transplantation. Am J Transplant. 2012;12(8):2052–61.

  62. 62.

    Li CX, Chen LL, Li XC, Ng KT, Yang XX, Lo CM, et al. ApoA-1 accelerates regeneration of small-for-size fatty liver graft after transplantation. Life Sci. 2018;215:128–35.

  63. 63.

    Liang S, Chen Y, Long F, Li J, Cheng M, Shi Y, et al. Correlation between augmenter of liver regeneration and IFN-γ expression in graft after rat orthotopic liver transplantation. J Surg Res. 2012;178(2):968–73.

  64. 64.

    Yang K, Du C, Cheng Y, Li Y, Gong J, Liu Z. Augmenter of liver regeneration promotes hepatic regeneration depending on the integrity of Kupffer cell in rat small-for-size liver transplantation. J Surg Res. 2013;183(2):922–8.

  65. 65.

    Luo HY, Ma SF, Qu JF, Tian DH. Effects of Kupffer cell inactivation on graft survival and liver regeneration after partial liver transplantation in rats. Hepatobiliary Pancreat Dis Int. 2015;14(1):56–62.

  66. 66.

    Eguchi S, Yanaga K, Sugiyama N, Okudaira S, Furui J, Kanematsu T. Relationship between portal venous flow and liver regeneration in patients after living donor right-lobe liver transplantation. Liver Transpl. 2003;9(6):547–51.

  67. 67.

    Tsang LC, Tung YC, Hsu HW, Ou HY, Yu CY, Huang TL, et al. Impact of graft type in living donor liver transplantation: remnant liver regeneration and outcome in donors. Transplant Proc. 2016;48(4):1015–7 Elsevier.

  68. 68.

    Kikuchi N, Yamaguchi Y, Mori K, Takata N, Goto M, Makino Y, et al. Effect of cyclosporine on liver regeneration after orthotopic reduced-size hepatic transplantation in the rat. Dig Dis Sci. 1993;38(8):1492–9.

  69. 69.

    Taki-Eldin A, Zhou L, Xie HY, Chen KJ, Zhou WH, Zhang W, et al. Tri-iodothyronine enhances liver regeneration after living donor liver transplantation in rats. J Hepatobiliary Pancreat Sci. 2011;18(6):806–14.

  70. 70.

    Bockhorn M, Fingas CD, Rauen U, Canbay A, Sotiropoulos GC, Frey U, et al. Erythropoietin treatment improves liver regeneration and survival in rat models of extended liver resection and living donor liver transplantation. Transplantation. 2008;86(11):1578–85.

  71. 71.

    • Papanikolaou IG, Katselis C, Apostolou K, Feretis T, Lymperi M, Konstadoulakis MM, et al. Mesenchymal stem cells transplantation following partial hepatectomy: a new concept to promote liver regeneration—systematic review of the literature focused on experimental studies in rodent models. Stem Cells Int. 2017;2017:7567958 Comprehensive overview of the role of stem cells in liver regeneration. Stem cells are extremely important in the repair, and they are the focus of much therapeutic research in this field.

  72. 72.

    de Miguel MP, Prieto I, Moratilla A, Arias J, Aller MA. Mesenchymal stem cells for liver regeneration in liver failure: from experimental models to clinical trials. Stem Cells Int. 2019;2019:3945672.

  73. 73.

    •• Apostolou KG, Papanikolaou IG, Katselis C, Feretis T, Kletsas D, Konstadoulakis MM, et al. Undifferentiated adipose tissue stem cell transplantation promotes hepatic regeneration, ameliorates histopathologic damage of the liver, and upregulates the expression of liver regeneration-and liver-specific genes in a rat model of partial hepatectomy. Stem Cells Int. 2018;2018:1393607 This is a study which investigated the effect of adipose tissue stem cells on the regenerative process. It provides insight into the roles of various types of stem cells in regeneration, which is important to current research on clinical implications of these cells.

  74. 74.

    Gomez D, Homer-Vanniasinkam S, Graham AM, Prasad KR. Role of ischaemic preconditioning in liver regeneration following major liver resection and transplantation. World J Gastroenterol: WJG. 2007;13(5):657–70.

  75. 75.

    Ahmad TA, Eguchi S, Yanaga K, Miyamoto S, Kamohara Y, Fujioka H, et al. Role of intrasplenic hepatocyte transplantation in improving survival and liver regeneration after hepatic resection in cirrhotic rats. Cell Transplant. 2002;11(5):399–402.

  76. 76.

    Chen Z, Chang R, Guan W, Cai H, Tang F, Zhu W, et al. Transplantation of porcine hepatocytes cultured with polylactic acid-o-carboxymethylated chitosan nanoparticles promotes liver regeneration in acute liver failure rats. J Drug Deliv. 2011;2011:797503.

  77. 77.

    Ito A, Higashiguchi T. Effects of glutamine administration on liver regeneration following hepatectomy. Nutrition. 1999;15(1):23–8.

  78. 78.

    Rigotti P, Peters JC, Tranberg KG, Fischer JE. Effects of amino acid infusions on liver regeneration after partial hepatectomy in the rat. J Parenter Enter Nutr. 1986;10(1):17–20.

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Correspondence to P. N. Martins.

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Hyslip, J., Martins, P.N. Liver Repair and Regeneration in Transplant: State of the Art. Curr Transpl Rep (2020). https://doi.org/10.1007/s40472-020-00269-z

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Keywords

  • Liver
  • Liver regeneration
  • Liver repair
  • Transplantation
  • Injury
  • Mechanisms