Surgery Today

, Volume 35, Issue 9, pp 705–710

Liver Repopulation: A New Concept of Hepatocyte Transplantation

  • Yujo Kawashita
  • Chandan Guha
  • Kosho Yamanouchi
  • Yuichiro Ito
  • Yukio Kamohara
  • Takashi Kanematsu
Review Article


Hepatocyte transplantation has been recognized as an alternative strategy for organ transplantation because the supply of donor livers is limited. However, in conventional hepatocyte transplantation, only 1%–10% of the liver replaced with transplanted hepatocytes. Recently a novel concept termed “liver repopulation” has been established, where the whole recipient liver can be replaced by a small number of donor hepatocytes. To induce liver repopulation, growth advantage of the donor hepatocytes against the host liver seems to be required according to the data of previous studies. Additionally, various cell sources, including bone marrow cells and other stem cells, could potentially be used as donor cells for liver repopulation. In this article, we discuss recent progress and future perspectives of this emerging technology.

Key words

Hepatocyte transplantation Liver repopulation 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Demetriou, AA, Reisner, A, Sanchez, J, Levenson, SM, Moscioni, AD, Chowdhury, JR 1988Transplantation of microcarrier-attached hepatocytes into 90% partially hepatectomized ratsHepatology810069PubMedGoogle Scholar
  2. 2.
    Baumgartner, D, LaPlante-O’Neill, PM, Sutherland, DE, Najarian, JS 1983Effects of intrasplenic injection of hepatocytes, hepatocyte fragments and hepatocyte culture supernatants on D-galactosamine-induced liver failure in ratsEur Surg Res1512935PubMedGoogle Scholar
  3. 3.
    Ribeiro, J, Nordlinger, B, Ballet, F, Cynober, L, Coudray-Lucas, C, Baudrimont, M,  et al. 1992Intrasplenic hepatocellular transplantation corrects hepatic encephalopathy in portacaval-shunted ratsHepatology15128PubMedGoogle Scholar
  4. 4.
    Gupta, S, Yerneni, PR, Vemuru, RP, Lee, CD, Yellin, EL, Bhargava, KK 1993Studies on the safety of intrasplenic hepatocyte transplantation: relevance to ex vivo gene therapy and liver repopulation in acute hepatic failureHum Gene Ther424957PubMedGoogle Scholar
  5. 5.
    Kobayashi, N, Ito, M, Nakamura, J, Cai, J, Gao, C, Hammel, JM,  et al. 2000Hepatocyte transplantation in rats with decompensated cirrhosisHepatology318517CrossRefPubMedGoogle Scholar
  6. 6.
    Ahmad, TA, Eguchi, S, Yanaga, K, Miyamoto, S, Kamohara, Y, Fujioka, H,  et al. 2002Role of intrasplenic hepatocyte transplantation in improving survival and liver regeneration after hepatic resection in cirrhotic ratsCell Transplant11399402PubMedGoogle Scholar
  7. 7.
    Mito, M, Kusano, M, Kawaura, Y 1992Hepatocyte transplantation in manTransplant Proc2430523PubMedGoogle Scholar
  8. 8.
    Habibullah, CM, Syed, IH, Qamar, A, Taher-Uz, Z 1994Human fetal hepatocyte transplantation in patients with fulminant hepatic failureTransplantation589512PubMedGoogle Scholar
  9. 9.
    Horslen, SP, McCowan, TC, Goertzen, TC, Warkentin, PI, Cai, HB, Strom, SC,  et al. 2003Isolated hepatocyte transplantation in an infant with a severe urea cycle disorderPediatrics11112627CrossRefPubMedGoogle Scholar
  10. 10.
    Fox, IJ, Chowdhury, JR, Kaufman, SS, Goertzen, TC, Chowdhury, NR, Warkentin, PI,  et al. 1998Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantationN Engl J Med33814226CrossRefPubMedGoogle Scholar
  11. 11.
    Chowdhury, JR, Grossman, M, Gupta, S, Chowdhury, NR, Baker, JR,Jr, Wilson, JM 1991Long-term improvement of hypercholesterolemia after ex vivo gene therapy in LDLR-deficient rabbitsScience25418025PubMedGoogle Scholar
  12. 12.
    Grossman, M, Raper, SE, Kozarsky, K, Stein, EA, Engelhardt, JF, Muller, D,  et al. 1994Successful ex vivo gene therapy directed to liver in a patient with familial hypercholesterolaemiaNat Genet633541CrossRefPubMedGoogle Scholar
  13. 13.
    Rozga, J, Holzman, M, Moscioni, AD, Fujioka, H, Morsiani, E, Demetriou, AA 1995Repeated intraportal hepatocyte transplantation in analbuminemic ratsCell Transplant423743CrossRefPubMedGoogle Scholar
  14. 14.
    Petersen, J, Dandri, M, Gupta, S, Rogler, CE 1998Liver repopulation with xenogenic hepatocytes in B and T cell-deficient mice leads to chronic hepadnavirus infection and clonal growth of hepatocellular carcinomaProc Natl Acad Sci USA953105CrossRefPubMedGoogle Scholar
  15. 15.
    Overturf, K, Al-Dhalimy, M, Manning, K, Ou, CN, Finegold, M, Grompe, M 1998Ex vivo hepatic gene therapy of a mouse model of hereditary tyrosinemia type IHum Gene Ther9295304PubMedGoogle Scholar
  16. 16.
    Laconi, E, Oren, R, Mukhopadhyay, DK, Hurston, E, Laconi, S, Pani, P,  et al. 1998Long-term, near-total liver replacement by transplantation of isolated hepatocytes in rats treated with retrorsineAm J Pathol15331929PubMedGoogle Scholar
  17. 17.
    Guha, C, Parashar, B, Deb, NJ, Garg, M, Gorla, GR, Singh, A,  et al. 2002Normal hepatocytes correct serum bilirubin after repopulation of Gunn rat liver subjected to irradiation/partial resectionHepatology3635462CrossRefPubMedGoogle Scholar
  18. 18.
    Takahashi, M, Deb, NJ, Kawashita, Y, Lee, SW, Furgueil, J, Okuyama, T,  et al. 2003A novel strategy for in vivo expansion of transplanted hepatocytes using preparative hepatic irradiation and FasL-induced hepatocellular apoptosisGene Ther1030413CrossRefPubMedGoogle Scholar
  19. 19.
    Fox, IJ, Chowdhury, NR, Gupta, S, Kondapalli, R, Schilsky, ML, Stockert, RJ,  et al. 1995Conditional immortalization of Gunn rat hepatocytes: an ex vivo model for evaluating methods for bilirubin-UDP-glucuronosyltransferase gene transferHepatology2183746CrossRefPubMedGoogle Scholar
  20. 20.
    Kobayashi, N, Fujiwara, T, Westerman, KA, Inoue, Y, Sakaguchi, M, Noguchi, H,  et al. 2000Prevention of acute liver failure in rats with reversibly immortalized human hepatocytesScience287125862CrossRefPubMedGoogle Scholar
  21. 21.
    Watanabe, FD, Mullon, CJ, Hewitt, WR, Arkadopoulos, N, Kahaku, E, Eguchi, S,  et al. 1997Clinical experience with a bioartificial liver in the treatment of severe liver failure. A phase I clinical trialAnn Surg22548491discussion 91–4CrossRefPubMedGoogle Scholar
  22. 22.
    Kanematsu, T, Eguchi, S 1998Hepatocyte-based bioartificial liver support: past, present and futureSurg Today284836CrossRefPubMedGoogle Scholar
  23. 23.
    van der Laan, LJ, Lockey, C, Griffeth, BC, Frasier, FS, Wilson, CA, Onions, DE,  et al. 2000Infection by porcine endogenous retrovirus after islet xenotransplantation in SCID miceNature407904CrossRefPubMedGoogle Scholar
  24. 24.
    Lagasse, E, Connors, H, Al-Dhalimy, M, Reitsma, M, Dohse, M, Osborne, L,  et al. 2000Purified hematopoietic stem cells can differentiate into hepatocytes in vivoNat Med6122934CrossRefPubMedGoogle Scholar
  25. 25.
    Strom, SC, Fisher, RA, Thompson, MT, Sanyal, AJ, Cole, PE, Ham, JM,  et al. 1997Hepatocyte transplantation as a bridge to orthotopic liver transplantation in terminal liver failureTransplantation6355969CrossRefPubMedGoogle Scholar
  26. 26.
    Bilir, BM, Guinette, D, Karrer, F, Kumpe, DA, Krysl, J, Stephens, J,  et al. 2000Hepatocyte transplantation in acute liver failureLiver Transpl63240PubMedGoogle Scholar
  27. 27.
    Grossman, M, Rader, DJ, Muller, DW, Kolansky, DM, Kozarsky, K, Clark, BJ,3rd,  et al. 1995A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolaemiaNat Med1114854CrossRefPubMedGoogle Scholar
  28. 28.
    Muraca, M, Gerunda, G, Neri, D, Vilei, MT, Granato, A, Feltracco, P,  et al. 2002Hepatocyte transplantation as a treatment for glycogen storage disease type 1aLancet3593178CrossRefPubMedGoogle Scholar
  29. 29.
    Sokal, EM, Smets, F, Bourgois, A, Van Maldergem, L, Buts, JP, Reding, R,  et al. 2003Hepatocyte transplantation in a 4-year-old girl with peroxisomal biogenesis disease: technique, safety, and metabolic follow-upTransplantation767358CrossRefPubMedGoogle Scholar
  30. 30.
    Moscioni, AD, Rozga, J, Chen, S, Naim, A, Scott, HS, Demetriou, AA 1996Long-term correction of albumin levels in the Nagase analbuminemic rat: repopulation of the liver by transplanted normal hepatocytes under a regeneration responseCell Transplant5499503CrossRefPubMedGoogle Scholar
  31. 31.
    Ilan, Y, Roy-Chowdhury, N, Prakash, R, Jona, V, Attavar, P, Guha, C,  et al. 1997Massive repopulation of rat liver by transplantation of hepatocytes into specific lobes of the liver and ligation of portal vein branches to other lobesTransplantation64813CrossRefPubMedGoogle Scholar
  32. 32.
    Mignon, A, Guidotti, JE, Mitchell, C, Fabre, M, Werent, A, De La Coste, A,  et al. 1998Selective repopulation of normal mouse liver by Fas/CD95-resistant hepatocytesNat Med411858CrossRefPubMedGoogle Scholar
  33. 33.
    Guha, C, Sharma, A, Gupta, S, Alfieri, A, Gorla, GR, Gagandeep, S,  et al. 1999Amelioration of radiation-induced liver damage in partially hepatectomized rats by hepatocyte transplantationCancer Res5958714PubMedGoogle Scholar
  34. 34.
    Oren, R, Dabeva, MD, Karnezis, AN, Petkov, PM, Rosencrantz, R, Sandhu, JP,  et al. 1999Role of thyroid hormone in stimulating liver repopulation in the rat by transplanted hepatocytesHepatology3090313CrossRefPubMedGoogle Scholar
  35. 35.
    Guo, D, Fu, T, Nelson, JA, Superina, RA, Soriano, HE 2002Liver repopulation after cell transplantation in mice treated with retrorsine and carbon tetrachlorideTransplantation73181824CrossRefPubMedGoogle Scholar
  36. 36.
    Malhi, H, Gorla, GR, Irani, AN, Annamaneni, P, Gupta, S 2002Cell transplantation after oxidative hepatic preconditioning with radiation and ischemia-reperfusion leads to extensive liver repopulationProc Natl Acad Sci USA99131149CrossRefPubMedGoogle Scholar
  37. 37.
    Mallet, VO, Mitchell, C, Mezey, E, Fabre, M, Guidotti, JE, Renia, L,  et al. 2002Bone marrow transplantation in mice leads to a minor population of hepatocytes that can be selectively amplified in vivoHepatology35799804CrossRefPubMedGoogle Scholar
  38. 38.
    Mitchell, C, Mallet, VO, Guidotti, JE, Goulenok, C, Kahn, A, Gilgenkrantz, H 2002Liver repopulation by Bcl-x(L) transgenic hepatocytesAm J Pathol160315PubMedGoogle Scholar
  39. 39.
    Yuan, RH, Ogawa, A, Ogawa, E, Neufeld, D, Zhu, L, Shafritz, DA 2003p27Kip1 inactivation provides a proliferative advantage to transplanted hepatocytes in DPPIV/Rag2 double knockout mice after repeated host liver injuryCell Transplant1290719PubMedGoogle Scholar
  40. 40.
    Suzuki, A, Zheng, YW, Fukao, K, Nakauchi, H, Taniguchi, H 2004Liver repopulation by c-Met-positive stem/progenitor cells isolated from the developing rat liverHepatogastroenterology514236PubMedGoogle Scholar

Copyright information

© Springer-Verlag Tokyo 2005

Authors and Affiliations

  • Yujo Kawashita
    • 1
  • Chandan Guha
    • 2
  • Kosho Yamanouchi
    • 2
  • Yuichiro Ito
    • 1
  • Yukio Kamohara
    • 1
  • Takashi Kanematsu
    • 1
  1. 1.Department of Transplantation, Digestive SurgeryNagasaki University Graduate School of Biomedical ScienceNagasakiJapan
  2. 2.Department of Radiation OncologyAlbert Einstein College of MedicineNew YorkUSA

Personalised recommendations