- Namita Roy-Chowdhury, PhD
Namita Roy-Chowdhury, PhD
- Professor of Medicine and Genetics
- Albert Einstein College of Medicine
- Jayanta Roy-Chowdhury, MD, MRCP
Jayanta Roy-Chowdhury, MD, MRCP
- Professor of Medicine and Genetics
- Albert Einstein College of Medicine
- Section Editor
- Robert S Brown, Jr, MD, MPH
Robert S Brown, Jr, MD, MPH
- Section Editor — Liver Transplantation
- Vice Chair, Transitions of Care, Department of Medicine
- Interim Chief, Division of Gastroenterology and Hepatology
- Weill Cornell Medical College
- Professor of Clinical Medicine, Columbia University College of Physicians & Surgeons
Advances in the understanding of hepatocyte engraftment and the remarkable proliferative potential of hepatocytes have brought liver cell transplantation to the doorstep of application in the treatment of inherited and acquired human diseases. Extensive animal experiments have shown that hepatocytes transplanted in the liver or at ectopic sites survive, function, and participate in the regenerative process. Because the host liver architecture remains intact following the integration of the engrafted hepatocytes in the liver cords, hepatocyte transplantation is metabolically less stressful than transplantation of the whole organ, and the consequences of graft loss are much less severe.
Hepatocyte transplantation has many potential applications. Therapeutic genes can be transferred into cultured hepatocytes, and the phenotypically modified cells can then be transplanted for ex vivo gene therapy. Such gene transfer could be used to replace a missing gene product, to prevent immune rejection, or to give the cells a proliferative advantage. Hepatocyte transplantation does not interfere with subsequent liver transplantation or gene therapy. Although the clinical efficacy of hepatocyte transplantation has been demonstrated, the shortage of good quality donor livers for hepatocyte isolation and the lack of dependable methods of cryopreservation will limit widespread clinical application of this method until further research overcomes these problems.
SCOPE OF HEPATOCYTE TRANSPLANTATION
Potential clinical applications of hepatocyte transplantation are listed in (table 1).
Treatment of inherited metabolic diseases — Missing gene products can be substituted by transplanting normal primary hepatocytes from allogeneic donors. This simple approach holds promise for diseases such as Crigler-Najjar syndrome type 1, urea cycle disorders, and coagulopathies, including hemophilias. (See "Crigler-Najjar syndrome" and "Inborn errors of metabolism: Classification", section on 'Urea cycle disorders' and "Genetics of the hemophilias".)
Hepatocytes used for gene therapy can be derived from a separate donor (allogeneic transplantation) or the recipient can serve as the donor, in which case the genetic defect needs to be corrected before transplantation (autologous transplantation). An advantage of autologous transplantation is that it does not require immunosuppression [1-3].To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Benedetti E, Kirby JP, Asolati M, et al. Intrasplenic hepatocyte allotransplantation in dalmation dogs with and without cyclosporine immunosuppression. Transplantation 1997; 63:1206.
- Ilan Y, Sauter B, Roy-Chowdhury N, et al. Expression of adenoviral E3 gene production in normal rat hepatocytes prevents their rejection upon transplantation into allogeneic Gunn rats (abstract). Hepatology 1997; 26:490A.
- Fabrega AJ, Bommineni VR, Blanchard J, et al. Amelioration of analbuminemia by transplantation of allogeneic hepatocytes in tolerized rats. Transplantation 1995; 59:1362.
- Fox IJ, Roy Chowdhury N, Roy Chowdhury J. Hepatocyte transplantation in liver failure and inherited metabolic disorders. In: Acute Liver Failure, Lee WM, Williams R (Eds), Cambridge University Press, UK 1997. p.285.
- Roger V, Balladur P, Honiger J, et al. Internal bioartificial liver with xenogeneic hepatocytes prevents death from acute liver failure: an experimental study. Ann Surg 1998; 228:1.
- Guha C, Sharma A, Gupta S, et al. Amelioration of radiation-induced liver damage in partially hepatectomized rats by hepatocyte transplantation. Cancer Res 1999; 59:5871.
- Bilir BM, Guinette D, Karrer F, et al. Hepatocyte transplantation in acute liver failure. Liver Transpl 2000; 6:32.
- Habibullah CM, Syed IH, Qamar A, Taher-Uz Z. Human fetal hepatocyte transplantation in patients with fulminant hepatic failure. Transplantation 1994; 58:951.
- Strom SC, Fisher RA, Thompson MT, et al. Hepatocyte transplantation as a bridge to orthotopic liver transplantation in terminal liver failure. Transplantation 1997; 63:559.
- Kobayashi N, Ito M, Nakamura J, et al. Hepatocyte transplantation improves liver function and prolongs survival in rats with decompensated liver cirrhosis. Transplant Proc 1999; 31:428.
- Overturf K, Al-Dhalimy M, Tanguay R, et al. Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tyrosinaemia type I. Nat Genet 1996; 12:266.
- Meyburg J, Das AM, Hoerster F, et al. One liver for four children: first clinical series of liver cell transplantation for severe neonatal urea cycle defects. Transplantation 2009; 87:636.
- Gramignoli R, Tahan V, Dorko K, et al. New potential cell source for hepatocyte transplantation: discarded livers from metabolic disease liver transplants. Stem Cell Res 2013; 11:563.
- Fox IJ, Chowdhury NR, Gupta S, et al. Conditional immortalization of Gunn rat hepatocytes: an ex vivo model for evaluating methods for bilirubin-UDP-glucuronosyltransferase gene transfer. Hepatology 1995; 21:837.
- Paillard F. Reversible cell immortalization with the Cre-lox system. Hum Gene Ther 1999; 10:1597.
- Kobayashi N, Fujiwara T, Westerman KA, et al. Prevention of acute liver failure in rats with reversibly immortalized human hepatocytes. Science 2000; 287:1258.
- Rhim JA, Sandgren EP, Palmiter RD, Brinster RL. Complete reconstitution of mouse liver with xenogeneic hepatocytes. Proc Natl Acad Sci U S A 1995; 92:4942.
- Khan AA, Shaik MV, Parveen N, et al. Human fetal liver-derived stem cell transplantation as supportive modality in the management of end-stage decompensated liver cirrhosis. Cell Transplant 2010; 19:409.
- Basma H, Soto-Gutiérrez A, Yannam GR, et al. Differentiation and transplantation of human embryonic stem cell-derived hepatocytes. Gastroenterology 2009; 136:990.
- Loh YH, Agarwal S, Park IH, et al. Generation of induced pluripotent stem cells from human blood. Blood 2009; 113:5476.
- Aasen T, Raya A, Barrero MJ, et al. Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat Biotechnol 2008; 26:1276.
- Sauer V, Tchaikovskaya T, Wang X, et al. Human Urinary Epithelial Cells as a Source of Engraftable Hepatocyte-Like Cells Using Stem Cell Technology. Cell Transplant 2016; 25:2221.
- Du Y, Wang J, Jia J, et al. Human hepatocytes with drug metabolic function induced from fibroblasts by lineage reprogramming. Cell Stem Cell 2014; 14:394.
- Huang P, Zhang L, Gao Y, et al. Direct reprogramming of human fibroblasts to functional and expandable hepatocytes. Cell Stem Cell 2014; 14:370.
- Chen Y, Li Y, Wang X, et al. Amelioration of Hyperbilirubinemia in Gunn Rats after Transplantation of Human Induced Pluripotent Stem Cell-Derived Hepatocytes. Stem Cell Reports 2015; 5:22.
- Lagasse E, Connors H, Al-Dhalimy M, et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med 2000; 6:1229.
- Thorgeirsson SS, Grisham JW. Hematopoietic cells as hepatocyte stem cells: a critical review of the evidence. Hepatology 2006; 43:2.
- Aurich H, Sgodda M, Kaltwasser P, et al. Hepatocyte differentiation of mesenchymal stem cells from human adipose tissue in vitro promotes hepatic integration in vivo. Gut 2009; 58:570.
- Huang P, He Z, Ji S, et al. Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors. Nature 2011; 475:386.
- Gupta S, Aragona E, Vemuru RP, et al. Permanent engraftment and function of hepatocytes delivered to the liver: implications for gene therapy and liver repopulation. Hepatology 1991; 14:144.
- Gupta S, Rajvanshi P, Lee CD. Integration of transplanted hepatocytes into host liver plates demonstrated with dipeptidyl peptidase IV-deficient rats. Proc Natl Acad Sci U S A 1995; 92:5860.
- Gupta S, Yerneni PR, Vemuru RP, et al. Studies on the safety of intrasplenic hepatocyte transplantation: relevance to ex vivo gene therapy and liver repopulation in acute hepatic failure. Hum Gene Ther 1993; 4:249.
- Ponder KP, Gupta S, Leland F, et al. Mouse hepatocytes migrate to liver parenchyma and function indefinitely after intrasplenic transplantation. Proc Natl Acad Sci U S A 1991; 88:1217.
- Kusano M, Mito M. Observations on the fine structure of long-survived isolated hepatocytes inoculated into rat spleen. Gastroenterology 1982; 82:616.
- Holzman MD, Rozga J, Neuzil DF, et al. Selective intraportal hepatocyte transplantation in analbuminemic and Gunn rats. Transplantation 1993; 55:1213.
- Dixit V, Arthur M, Reinhardt R, Gitnick G. Improved function of microencapsulated hepatocytes in a hybrid bioartificial liver support system. Artif Organs 1992; 16:336.
- Demetriou AA, Reisner A, Sanchez J, et al. Transplantation of microcarrier-attached hepatocytes into 90% partially hepatectomized rats. Hepatology 1988; 8:1006.
- Honiger J, Balladur P, Mariani P, et al. Permeability and biocompatibility of a new hydrogel used for encapsulation of hepatocytes. Biomaterials 1995; 16:753.
- Matas AJ, Sutherland DE, Steffes MW, et al. Hepatocellular transplantation for metabolic deficiencies: decrease of plasms bilirubin in Gunn rats. Science 1976; 192:892.
- Groth CG, Arborgh B, Björkén C, et al. Correction of hyperbilirubinemia in the glucuronyltransferase-deficient rat by intraportal hepatocyte transplantation. Transplant Proc 1977; 9:313.
- Guha C, Parashar B, Deb NJ, et al. Normal hepatocytes correct serum bilirubin after repopulation of Gunn rat liver subjected to irradiation/partial resection. Hepatology 2002; 36:354.
- Yamanouchi K, Zhou H, Roy-Chowdhury N, et al. Hepatic irradiation augments engraftment of donor cells following hepatocyte transplantation. Hepatology 2009; 49:258.
- Rozga J, Holzman M, Moscioni AD, et al. Repeated intraportal hepatocyte transplantation in analbuminemic rats. Cell Transplant 1995; 4:237.
- Gunsalus JR, Brady DA, Coulter SM, et al. Reduction of serum cholesterol in Watanabe rabbits by xenogeneic hepatocellular transplantation. Nat Med 1997; 3:48.
- Yoshida Y, Tokusashi Y, Lee GH, Ogawa K. Intrahepatic transplantation of normal hepatocytes prevents Wilson's disease in Long-Evans cinnamon rats. Gastroenterology 1996; 111:1654.
- De Vree JM, Ottenhoff R, Bosma PJ, et al. Correction of liver disease by hepatocyte transplantation in a mouse model of progressive familial intrahepatic cholestasis. Gastroenterology 2000; 119:1720.
- Baumgartner D, LaPlante-O'Neill PM, Sutherland DE, Najarian JS. Effects of intrasplenic injection of hepatocytes, hepatocyte fragments and hepatocyte culture supernatants on D-galactosamine-induced liver failure in rats. Eur Surg Res 1983; 15:129.
- Braun KM, Degen JL, Sandgren EP. Hepatocyte transplantation in a model of toxin-induced liver disease: variable therapeutic effect during replacement of damaged parenchyma by donor cells. Nat Med 2000; 6:320.
- Ribeiro J, Nordlinger B, Ballet F, et al. Intrasplenic hepatocellular transplantation corrects hepatic encephalopathy in portacaval-shunted rats. Hepatology 1992; 15:12.
- Cai J, Ito M, Nagata H, et al. Treatment of liver failure in rats with end-stage cirrhosis by transplantation of immortalized hepatocytes. Hepatology 2002; 36:386.
- Petersen J, Dandri M, Gupta S, Rogler CE. Liver repopulation with xenogenic hepatocytes in B and T cell-deficient mice leads to chronic hepadnavirus infection and clonal growth of hepatocellular carcinoma. Proc Natl Acad Sci U S A 1998; 95:310.
- Overturf K, Al-Dhalimy M, Manning K, et al. Ex vivo hepatic gene therapy of a mouse model of Hereditary Tyrosinemia Type I. Hum Gene Ther 1998; 9:295.
- De Vree JM, Ottenhoff R, Smith AJ. Rapid correction of Mdr 2 deficiency by transplantation of MDR3 transgenic hepatocytes. Hepatology Supp 1998; 28:4.
- Ding J, Yannam GR, Roy-Chowdhury N, et al. Spontaneous hepatic repopulation in transgenic mice expressing mutant human α1-antitrypsin by wild-type donor hepatocytes. J Clin Invest 2011; 121:1930.
- Laconi E, Oren R, Mukhopadhyay DK, et al. Long-term, near-total liver replacement by transplantation of isolated hepatocytes in rats treated with retrorsine. Am J Pathol 1998; 153:319.
- Guha C, Parashar B, Roy Chowdhury N, et al. Complete, long-term normalization of serum bilirubin levels in Gunn rats after hepatocyte transplantation following partial hepatectomy and liver irradiation. Hepatology Supp 1999; 30:108.
- Chowdhury JR, Grossman M, Gupta S, et al. Long-term improvement of hypercholesterolemia after ex vivo gene therapy in LDLR-deficient rabbits. Science 1991; 254:1802.
- Oertel M, Rosencrantz R, Chen YQ, et al. Repopulation of rat liver by fetal hepatoblasts and adult hepatocytes transduced ex vivo with lentiviral vectors. Hepatology 2003; 37:994.
- Horslen SP, McCowan TC, Goertzen TC, et al. Isolated hepatocyte transplantation in an infant with a severe urea cycle disorder. Pediatrics 2003; 111:1262.
- Stéphenne X, Najimi M, Smets F, et al. Cryopreserved liver cell transplantation controls ornithine transcarbamylase deficient patient while awaiting liver transplantation. Am J Transplant 2005; 5:2058.
- Stéphenne X, Najimi M, Sibille C, et al. Sustained engraftment and tissue enzyme activity after liver cell transplantation for argininosuccinate lyase deficiency. Gastroenterology 2006; 130:1317.
- Strom SC, Fisher RA, Rubinstein WS, et al. Transplantation of human hepatocytes. Transplant Proc 1997; 29:2103.
- Fox IJ, Chowdhury JR, Kaufman SS, et al. Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantation. N Engl J Med 1998; 338:1422.
- Mitry RR, Dhawan A, Hughes RD, et al. One liver, three recipients: segment IV from split-liver procedures as a source of hepatocytes for cell transplantation. Transplantation 2004; 77:1614.
- Grossman M, Raper SE, Kozarsky K, et al. Successful ex vivo gene therapy directed to liver in a patient with familial hypercholesterolaemia. Nat Genet 1994; 6:335.
- Azuma H, Paulk N, Ranade A, et al. Robust expansion of human hepatocytes in Fah-/-/Rag2-/-/Il2rg-/- mice. Nat Biotechnol 2007; 25:903.
- Zhou H, Dong X, Kabarriti R, et al. Single liver lobe repopulation with wildtype hepatocytes using regional hepatic irradiation cures jaundice in Gunn rats. PLoS One 2012; 7:e46775.
- Landis CS, Yamanouchi K, Zhou H, et al. Noninvasive evaluation of liver repopulation by transplanted hepatocytes using 31P MRS imaging in mice. Hepatology 2006; 44:1250.
- Hathcock KS, Laszlo G, Dickler HB, et al. Identification of an alternative CTLA-4 ligand costimulatory for T cell activation. Science 1993; 262:905.
- Wallace PM, Rodgers JN, Leytze GM, et al. Induction and reversal of long-lived specific unresponsiveness to a T-dependent antigen following CTLA4Ig treatment. J Immunol 1995; 154:5885.
- Mashalova EV, Guha C, Roy-Chowdhury N, et al. Prevention of hepatocyte allograft rejection in rats by transferring adenoviral early region 3 genes into donor cells. Hepatology 2007; 45:755.
- SCOPE OF HEPATOCYTE TRANSPLANTATION
- Treatment of inherited metabolic diseases
- Management of acute liver failure
- Management of chronic liver failure
- SOURCES OF HEPATOCYTES
- SITES OF HEPATOCYTE TRANSPLANTATION
- PRECLINICAL EVALUATION IN EXPERIMENTAL ANIMAL MODELS
- Disorders due to single gene defects
- Acute and chronic liver failure
- Massive repopulation of the liver
- Ex vivo gene therapy
- CLINICAL EXPERIENCE
- Metabolic disorders
- Liver failure
- Ex vivo gene therapy
- BARRIERS AND ADDITIONAL RESEARCH