- 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].
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- 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.
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- 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.
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- De Vree, JM, Ottenhoff, R, Smith, AJ, et al. 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.
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- 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