Hepatocyte Transplantation

  • Mirela-Patricia Sirbu-Boeti
  • Kyle Soltys
  • Alejandro Soto-Gutierrez
  • Ira J. Fox
Part of the Molecular Pathology Library book series (MPLB, volume 5)


The scientific foundation for clinical hepatocyte transplantation was developed over the last 40 years by extensive laboratory work in animals. The first attempts at human hepatocyte transplantation were performed by Mito et al. who used autologous hepatocytes to treat patients with chronic liver disease [1]. Habibullah et al. [2] later transplanted allogeneic fetal hepatocytes to treat patients with fulminant hepatic failure. The first attempted treatment of a metabolic disorder was performed in patients with familial hypercholesterolemia using autologous retrovirus-transduced hepatocytes by Grossman et al. [3]. Several years later, allogenic hepatocytes were used to treat a different metabolic liver disorder with some success in a patient with Crigler-Najjar syndrome type I [4].


Orthotopic Liver Transplantation Biliary Atresia Acute Liver Failure Familial Hypercholesterolemia Fetal Liver Cell 
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.


  1. 1.
    Mito M, Kusano M, Kawaura Y. Hepatocyte transplantation in man. Transplant Proc. 1992;24:3052–3.PubMedGoogle Scholar
  2. 2.
    Habibullah CM, Syed IH, Qamar A, Taher-Uz Z. Human fetal hepatocyte transplantation in patients with fulminant hepatic failure. Transplantation. 1994;58:951–2.PubMedCrossRefGoogle Scholar
  3. 3.
    Grossman M et al. Successful ex vivo gene therapy directed to liver in a patient with familial hypercholesterolaemia. Nat Genet. 1994;6:335–41.PubMedCrossRefGoogle Scholar
  4. 4.
    Fox IJ et al. Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantation. N Engl J Med. 1998;338:1422–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Fisher RA, Strom SC. Human hepatocyte transplantation: worldwide results. Transplantation. 2006;82:441–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Raghuveer TS, Garg U, Graf WD. Inborn errors of metabolism in infancy and early childhood: an update. Am Fam Physician. 2006;73:1981–90.PubMedGoogle Scholar
  7. 7.
    Sokal EM. Liver transplantation for inborn errors of liver metabolism. J Inherit Metab Dis. 2006;29:426–30.PubMedCrossRefGoogle Scholar
  8. 8.
    Otsuka Y et al. Postresection hepatic failure: successful treatment with liver transplantation. Liver Transpl. 2007;13:672–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Garcea G, Maddern GJ. Liver failure after major hepatic resection. J Hepatobiliary Pancreat Surg. 2009;16:145–55.PubMedCrossRefGoogle Scholar
  10. 10.
    Strom SC, Chowdhury JR, Fox IJ. Hepatocyte transplantation for the treatment of human disease. Semin Liver Dis. 1999;19:39–48.PubMedCrossRefGoogle Scholar
  11. 11.
    Smets F, Najimi M, Sokal EM. Cell transplantation in the treatment of liver diseases. Pediatr Transplant. 2008;12:6–13.PubMedCrossRefGoogle Scholar
  12. 12.
    Baccarani U et al. Isolation of human hepatocytes from livers rejected for liver transplantation on a national basis: results of a 2-year experience. Liver Transpl. 2003;9:506–12.PubMedCrossRefGoogle Scholar
  13. 13.
    Bilir BM et al. Hepatocyte transplantation in acute liver failure. Liver Transpl. 2000;6:32–40.PubMedGoogle Scholar
  14. 14.
    Baccarani U et al. Steatotic versus cirrhotic livers as a source for human hepatocyte isolation. Transplant Proc. 2001;33:664–5.PubMedCrossRefGoogle Scholar
  15. 15.
    Hewitt WR et al. Isolation of human hepatocytes from livers rejected for whole organ transplantation. Transplant Proc. 1997;29:1945–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Adam R, Hoti E. Liver transplantation: the current situation. Semin Liver Dis. 2009;29:3–18.PubMedCrossRefGoogle Scholar
  17. 17.
    Mitry RR et al. One liver, three recipients: segment IV from split-liver procedures as a source of hepatocytes for cell transplantation. Transplantation. 2004;77:1614–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Haghighi KS et al. A new source of hepatocytes for transplantation. Transplant Proc. 2004;36:2466–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Tolboom H et al. Recovery of warm ischemic rat liver grafts by normothermic extracorporeal perfusion. Transplantation. 2009;87:170–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Cai J et al. Treatment of liver failure in rats with end-stage cirrhosis by transplantation of immortalized hepatocytes. Hepatology. 2002;36:386–94.PubMedCrossRefGoogle Scholar
  21. 21.
    Kobayashi N et al. Cre/loxP-based reversible immortalization of human hepatocytes. Cell Transplant. 2001;10:383–6.PubMedGoogle Scholar
  22. 22.
    Kobayashi N et al. Prevention of acute liver failure in rats with reversibly immortalized human hepatocytes. Science. 2000;287:1258–62.PubMedCrossRefGoogle Scholar
  23. 23.
    Wege H et al. Telomerase reconstitution immortalizes human fetal hepatocytes without disrupting their differentiation potential. Gastroenterology. 2003;124:432–44.PubMedCrossRefGoogle Scholar
  24. 24.
    Selden C, Hodgson H. Cellular therapies for liver replacement. Transplant Immunol. 2004;12:273–88.CrossRefGoogle Scholar
  25. 25.
    Ito M, Nagata H, Miyakawa S, Fox IJ. Review of hepatocyte transplantation. J Hepatobiliary Pancreat Surg. 2009;16:97–100.PubMedCrossRefGoogle Scholar
  26. 26.
    Wu Y, Shatapathy CC, Minger SL. Isolation, in vitro cultivation and characterisation of foetal liver cells. Methods Mol Biol. 2009;481:181–92.PubMedGoogle Scholar
  27. 27.
    Oertel M et al. Purification of fetal liver stem/progenitor cells containing all the repopulation potential for normal adult rat liver. Gastroenterology. 2008;134:823–32.PubMedCrossRefGoogle Scholar
  28. 28.
    Dabeva MD, Shafritz DA. Activation, proliferation, and differentiation of progenitor cells into hepatocytes in the D-galactosamine model of liver regeneration. Am J Pathol. 1993;143:1606–20.PubMedGoogle Scholar
  29. 29.
    Dan YY et al. Isolation of multipotent progenitor cells from human fetal liver capable of differentiating into liver and mesenchymal lineages. Proc Natl Acad Sci U S A. 2006;27:9912–7.CrossRefGoogle Scholar
  30. 30.
    Khan AA et al. Management of hyperbilirubinemia in biliary atresia by hepatic progenitor cell transplantation through hepatic artery: a case report. Transplant Proc. 2008;40:1153–5.PubMedCrossRefGoogle Scholar
  31. 31.
    Sokal EM et al. Hepatocyte transplantation in a 4-year-old girl with peroxisomal biogenesis disease: technique, safety, and metabolic follow-up. Transplantation. 2003;76:735–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Basma H et al. Differentiation and transplantation of human embryonic stem cell-derived hepatocytes. Gastroenterology. 2009;136:990–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Berry MN, Phillips JW. The isolated hepatocyte preparation: 30 years on. Biochem Soc Trans. 2000;28:131–5.PubMedGoogle Scholar
  34. 34.
    Berry MN, Friend DS. High-yield preparation of isolated rat liver parenchymal cells: a biochemical and fine structural study. J Cell Biol. 1969;43:506–20.PubMedCrossRefGoogle Scholar
  35. 35.
    Mitaka T, Mizuguchi T, Sato F, Mochisuki C, Mochizuki Y. Growth and maturation of small hepatocytes. J Gastroenterol Hepatol. 1998;13(Suppl):S70–7.PubMedGoogle Scholar
  36. 36.
    Runge D et al. Serum-free, long-term cultures of human hepatocytes: maintenance of cell morphology, transcription factors, and liver-specific functions. Biochem Biophys Res Commun. 2000;269:46–53.PubMedCrossRefGoogle Scholar
  37. 37.
    Alexandrova K et al. Large-scale isolation of human hepatocytes for therapeutic application. Cell Transplant. 2005;14:845–53.PubMedCrossRefGoogle Scholar
  38. 38.
    Mitry RR et al. Human hepatocyte isolation and relationship of cell viability to early graft function. Cell Transplant. 2003;12:69–74.PubMedCrossRefGoogle Scholar
  39. 39.
    Hughes RD, Mitry RR, Dhawan A. Hepatocyte transplantation for metabolic liver disease: UK experience. J R Soc Med. 2005;98:341–5.PubMedCrossRefGoogle Scholar
  40. 40.
    Mito M. The current and future aspects of liver cell transplantation. Nippon Geka Gakkai Zasshi. 1985;86:993–6.PubMedGoogle Scholar
  41. 41.
    Terry C, Hughes RD, Mitry RR, Lehec SC, Dhawan A. Cryopreservation-induced nonattachment of human hepatocytes: role of adhesion molecules. Cell Transplant. 2007;16:639–47.PubMedGoogle Scholar
  42. 42.
    Terry C et al. The effects of cryopreservation on human hepatocytes obtained from different sources of liver tissue. Cell Transplant. 2005;14:585–94.PubMedCrossRefGoogle Scholar
  43. 43.
    Puppi J, Dhawan A. Human hepatocyte transplantation overview. Methods Mol Biol. 2009;481:1–16.PubMedCrossRefGoogle Scholar
  44. 44.
    Diener B, Utesch D, Beer N, et al. A method for the cryopreservation of liver parenchymal cells for studies of xenobiotics. Cryobiology. 1993;30:116–27.PubMedCrossRefGoogle Scholar
  45. 45.
    Hengstler JG et al. Cryopreserved primary hepatocytes as a constantly available in vitro model for evaluation of human and animal drug metabolism and enzyme induction. Drug Metab Rev. 2000;32:81–118.PubMedCrossRefGoogle Scholar
  46. 46.
    Tanaka K et al. Functional hepatocyte culture and its application to cell therapies. Cell Transplant. 2006;15:855–64.PubMedCrossRefGoogle Scholar
  47. 47.
    Lehec SC et al. Experience of microbiological screening of human hepatocytes for clinical transplantation. Cell Transplant. 2009;18:941–7.PubMedCrossRefGoogle Scholar
  48. 48.
    Mitry RR, Hughes RD, Dhawan A. Progress in human hepatocytes: isolation, culture & cryopreservation. Semin Cell Dev Biol. 2002;13:463–7.PubMedCrossRefGoogle Scholar
  49. 49.
    Donato MT et al. Functional assessment of the quality of human hepatocyte preparations for cell transplantation. Cell Transplant. 2008;17:1211–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Horslen SP, Fox IJ. Hepatocyte transplantation. Transplantation. 2004;77:1481–6.PubMedCrossRefGoogle Scholar
  51. 51.
    Grossman M et al. A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolaemia. Nat Med. 1995;1:1148–54.PubMedCrossRefGoogle Scholar
  52. 52.
    Nussler A et al. Present status and perspectives of cell-based therapies for liver diseases. J Hepatol. 2006;45:144–59.PubMedCrossRefGoogle Scholar
  53. 53.
    Kerr A, Rajvanshi P, Gupta S. Percutaneous transcatheter liver cell transplantation: an emerging modality and its clinical implications. J Vasc Interv Radiol. 1996;7:169–76.PubMedCrossRefGoogle Scholar
  54. 54.
    Horslen SP et al. Isolated hepatocyte transplantation in an infant with a severe urea cycle disorder. Pediatrics. 2003;111:1262–7.PubMedCrossRefGoogle Scholar
  55. 55.
    Meyburg J, Hoerster F, Weitz J, Hoffmann GF, Schmidt J. Use of the middle colic vein for liver cell transplantation in infants and small children. Transplant Proc. 2008;40:936–7.PubMedCrossRefGoogle Scholar
  56. 56.
    Strom SC et al. Hepatocyte transplantation as a bridge to orthotopic liver transplantation in terminal liver failure. Transplantation. 1997;63:559–69.PubMedCrossRefGoogle Scholar
  57. 57.
    Muraca M, Burlina AB. Liver and liver cell transplantation for glycogen storage disease type IA. Acta Gastroenterol Belg. 2005;68:469–72.PubMedGoogle Scholar
  58. 58.
    Gupta S et al. Entry and integration of transplanted hepatocytes in rat liver plates occur by disruption of hepatic sinusoidal endothelium. Hepatology. 1999;29:509–19.PubMedCrossRefGoogle Scholar
  59. 59.
    Fisher RA, Bu D, Thompson M, Wolfe L, Ritter JK. Optimization of conditions for clinical human hepatocyte infusion. Cell Transplant. 2004;13:677–89.PubMedCrossRefGoogle Scholar
  60. 60.
    Sterling RK, Fisher RA. Liver transplantation. Living donor, hepatocyte, and xenotransplantation. Clin Liver Dis. 2001;5:431–60, vii.Google Scholar
  61. 61.
    Kumaran V, Joseph B, Benten D, Gupta S. Integrin and extracellular matrix interactions regulate engraftment of transplanted hepatocytes in the rat liver. Gastroenterology. 2005;129:1643–53.PubMedCrossRefGoogle Scholar
  62. 62.
    Rajvanshi P, Kerr A, Bhargava KK, Burk RD, Gupta S. Studies of liver repopulation using the dipeptidyl peptidase IV-deficient rat and other rodent recipients: cell size and structure relationships regulate capacity for increased transplanted hepatocyte mass in the liver lobule. Hepatology. 1996;23:482–96.PubMedCrossRefGoogle Scholar
  63. 63.
    Malhi H et al. Cyclophosphamide disrupts hepatic sinusoidal endothelium and improves transplanted cell engraftment in rat liver. Hepatology. 2002;36:112–21.PubMedCrossRefGoogle Scholar
  64. 64.
    Slehria S et al. Hepatic sinusoidal vasodilators improve transplanted cell engraftment and ameliorate microcirculatory perturbations in the liver. Hepatology. 2002;35:1320–8.PubMedCrossRefGoogle Scholar
  65. 65.
    Grompe M. Liver repopulation for the treatment of metabolic diseases. J Inherit Metab Dis. 2001;24:231–44.PubMedCrossRefGoogle Scholar
  66. 66.
    Laconi E, Laconi S. Principles of hepatocyte repopulation. Semin Cell Dev Biol. 2002;13:433–8.PubMedCrossRefGoogle Scholar
  67. 67.
    Guha C et al. Liver irradiation: a potential preparative regimen for hepatocyte transplantation. Int J Radiat Oncol Biol Phys. 2001;49:451–7.PubMedCrossRefGoogle Scholar
  68. 68.
    Yamanouchi K et al. Hepatic irradiation augments engraftment of donor cells following hepatocyte transplantation. Hepatology. 2009;49:258–67.PubMedCrossRefGoogle Scholar
  69. 69.
    Dhawan A, Mitry RR, Hughes RD. Hepatocyte transplantation for metabolic disorders, experience at King’s College hospital and review of literature. Acta Gastroenterol Belg. 2005;68:457–60.PubMedGoogle Scholar
  70. 70.
    Benoist S et al. Survival and differentiation of porcine hepatocytes encapsulated by semiautomatic device and allotransplanted in large number without immunosuppression. J Hepatol. 2001;35:208–16.PubMedCrossRefGoogle Scholar
  71. 71.
    Sarkis R et al. Intraperitoneal transplantation of isolated hepatocytes of the pig: the implantable bioartificial liver. Chirurgie. 1998;123:41–6.PubMedCrossRefGoogle Scholar
  72. 72.
    Demetriou AA et al. Survival, organization, and function of microcarrier-attached hepatocytes transplanted in rats. Proc Natl Acad Sci U S A. 1986;83:7475–9.PubMedCrossRefGoogle Scholar
  73. 73.
    Wang LJ et al. Engraftment assessment in human and mouse liver tissue after sex-mismatched liver cell transplantation by real-time quantitative PCR for Y chromosome sequences. Liver Transpl. 2002;8:822–8.PubMedCrossRefGoogle Scholar
  74. 74.
    Fisher RA et al. Defining hepatocellular chimerism in a liver failure patient bridged with hepatocyte infusion. Transplantation. 2000;69:303–7.PubMedCrossRefGoogle Scholar
  75. 75.
    Lafferty KJ, Prowse SJ, Simeonovic CJ, Warren HS. Immunobiology of tissue transplantation: a return to the passenger leukocyte concept. Annu Rev Immunol. 1983;1:143–73.PubMedCrossRefGoogle Scholar
  76. 76.
    Keller GA, West MA, Wilkes LA, Cerra FB, Simmons RL. Modulation of hepatocyte protein synthesis by endotoxin-activated Kupffer cells. II. Mediation by soluble transferrable factors. Ann Surg. 1985;201:429–35.PubMedCrossRefGoogle Scholar
  77. 77.
    Brent L et al. The antigenicity of purified liver parenchyma cells. Transplant Proc. 1981;13:860–2.PubMedGoogle Scholar
  78. 78.
    Herkel J et al. MHC class II-expressing hepatocytes function as antigen-presenting cells and activate specific CD4 T lymphocyutes. Hepatology. 2003;37:1079–85.PubMedCrossRefGoogle Scholar
  79. 79.
    Makowka L et al. Allogeneic hepatocyte transplantation in the rat spleen under cyclosporine immunosuppression. Transplantation. 1986;42:537–41.PubMedCrossRefGoogle Scholar
  80. 80.
    Bumgardner GL, Li J, Prologo JD, Heininger M, Orosz CG. Patterns of immune responses evoked by allogeneic hepatocytes: evidence for independent co-dominant roles for CD4+ and CD8+ T-cell responses in acute rejection. Transplantation. 1999;68:555–62.PubMedCrossRefGoogle Scholar
  81. 81.
    Gewartowska M, Olszewski WL. Hepatocyte transplantation-biology and application. Ann Transplant. 2007;12:27–36.PubMedGoogle Scholar
  82. 82.
    Olszewski WL, Jasklowska-Englisz M, Interewicz B. Hepatocyte transplantation-granulocytes recognize surface of isolated autologous hepatocytes as non-self and destroy them. Transplant Proc. 1997;29:1113–5.PubMedCrossRefGoogle Scholar
  83. 83.
    Han B, Lu Y, Meng B, Qu B. Cellular loss after allogenic hepatocyte transplantation. Transplantation. 2009;87:1–5.PubMedCrossRefGoogle Scholar
  84. 84.
    Morita H et al. Acceptance of skin allografts in pigs by portal venous injection of donor bone marrow cells. Ann Surg. 1999;230:114–9.PubMedCrossRefGoogle Scholar
  85. 85.
    Qian J, Hashimoto T, Fujiwara H, Hamaoka T. Studies on the induction of tolerance to alloantigens. I. The abrogation of potentials for delayed-type-hypersensitivity response to alloantigens by portal venous inoculation with allogeneic cells. J Immunol. 1985;134:3656–61.PubMedGoogle Scholar
  86. 86.
    van Poll D et al. Mesenchymal stem cell-derived molecules directly modulate hepatocellular death and regeneration in vitro and in vivo. Hepatology. 2008;47:1634–43.PubMedCrossRefGoogle Scholar
  87. 87.
    Mashalova EV et al. Prevention of hepatocyte allograft rejection in rats by transferring adenoviral early region 3 genes into donor cells. Hepatology. 2007;45:755–66.PubMedCrossRefGoogle Scholar
  88. 88.
    Olthoff KM et al. Adenovirus-mediated gene transfer into cold-preserved liver allografts: survival pattern and unresponsiveness following transduction with CTLA4Ig. Nat Med. 1998;4:194–200.PubMedCrossRefGoogle Scholar
  89. 89.
    Feng S et al. Prolonged xenograft survival of islets infected with small doses of adenovirus expressing CTLA4Ig. Transplantation. 1999;67:1607–13.PubMedCrossRefGoogle Scholar
  90. 90.
    Benedetti E et al. Intrasplenic hepatocyte allotransplantation in dalmation dogs with and without cyclosporine immunosuppression. Transplantation. 1997;63:1206–9.PubMedCrossRefGoogle Scholar
  91. 91.
    Goebel J, Stevens E, Forrest K, Roszman TL. Daclizumab (Zenapax) inhibits early interleukin-2 receptor signal transduction events. Transpl Immunol. 2000;8:153–9.PubMedCrossRefGoogle Scholar
  92. 92.
    Platz KP et al. RS-61443 – a new, potent immunosuppressive agent. Transplantation. 1991;51:27–31.PubMedCrossRefGoogle Scholar
  93. 93.
    Strom SC et al. Hepatocyte transplantation: clinical experience and potential for future use. Cell Transplant. 2006;15 Suppl 1:S105–10.PubMedCrossRefGoogle Scholar
  94. 94.
    Lee WM, Squires Jr RH, Nyberg SL, Doo E, Hoofnagle JH. Acute liver failure: Summary of a workshop. Hepatology. 2008;47:1401–15.PubMedCrossRefGoogle Scholar
  95. 95.
    Malhi H, Joseph B, Schilsky ML, Gupta S. Development of cell therapy strategies to overcome copper toxicity in the LEC rat model of Wilson disease. Regen Med. 2008;3:165–73.PubMedCrossRefGoogle Scholar
  96. 96.
    Ambrosino G et al. Isolated hepatocyte transplantation for Crigler-Najjar syndrome type 1. Cell Transplant. 2005;14:151–7.PubMedCrossRefGoogle Scholar
  97. 97.
    Puppi J et al. Hepatocyte transplantation followed by auxiliary liver transplantation – a novel treatment for ornithine transcarbamylase deficiency. Am J Transplant. 2008;8:452–7.PubMedCrossRefGoogle Scholar
  98. 98.
    Strom SC et al. Transplantation of human hepatocytes. Transplant Proc. 1997;29:2103–6.PubMedCrossRefGoogle Scholar
  99. 99.
    Stephenne X et al. Sustained engraftment and tissue enzyme activity after liver cell transplantation for argininosuccinate lyase deficiency. Gastroenterology. 2006;130:1317–23.PubMedCrossRefGoogle Scholar
  100. 100.
    Dhawan A et al. Hepatocyte transplantation for inherited factor VII deficiency. Transplantation. 2004;78:1812–4.PubMedCrossRefGoogle Scholar
  101. 101.
    Dhawan A, Mitry RR, Hughes RD. Hepatocyte transplantation for liver-based metabolic disorders. J Inherit Metab Dis. 2006;29:431–5.PubMedCrossRefGoogle Scholar
  102. 102.
    Squires Jr RH et al. Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group. J Pediatr. 2006;148:652–8.PubMedCrossRefGoogle Scholar
  103. 103.
    Schneider A et al. Hepatocyte transplantation in an acute liver failure due to mushroom poisoning. Transplantation. 2006;82:1115–6.PubMedCrossRefGoogle Scholar
  104. 104.
    Khan AA, Habeeb A, Parveen N, et al. Peritoneal transplantation of human fetal hepatocytes for the treatment of acute fatty liver of pregnancy: a case report. Trop Gastroenterol. 2004;25:141–3.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Mirela-Patricia Sirbu-Boeti
  • Kyle Soltys
  • Alejandro Soto-Gutierrez
  • Ira J. Fox
    • 1
  1. 1.Department of SurgeryUniversity of PittsburghPittsburghUSA

Personalised recommendations