Since the first human hepatocyte transplants (HTx) in 1992, clinical studies have clearly established proof of principle for this therapy as a treatment for patients with acquired or inherited liver disease. Although major accomplishments have been made, there are still some specific limitations to this technology, which, if overcome, could greatly enhance the efficacy and implementation of this therapy. Here, we describe what in our view are the most significant obstacles to the clinical application of HTx and review the solutions currently proposed. The obstacles of significance include the limited number and quality of liver tissues as a cell source, the lack of clinical grade reagents, quality control evaluation of hepatocytes prior to transplantation, hypothermic storage of cells prior to transplantation, preconditioning treatments to enhance engraftment and proliferation of donor cells, tracking or monitoring cells after transplantation, and the optimal immunosuppression protocols for transplant recipients.

Keywords:
Hepatocyte transplantation, Human hepatocytes, Metabolic liver disease, Cell-based therapy, Regenerative medicine
1.
Starzl TE, Marchioro TL, Vonkaulla KN, Hermann G, Brittain RS, Waddell WR: Homotransplantation of the liver in humans. Surg Gynecol Obstet 1963;117:659-676.
2.
Strom SC, Fisher RA, Rubinstein WS, Barranger JA, Towbin RB, Charron M, Mieles L, Pisarov LA, Dorko K, Thompson MT, Reyes J: Transplantation of human hepatocytes. Transplant Proc 1997;29:2103-2106.
3.
Strom SC, Fisher RA, Thompson MT, Sanyal AJ, Cole PE, Ham JM, Posner MP: Hepatocyte transplantation as a bridge to orthotopic liver transplantation in terminal liver failure. Transplantation 1997;63:559-569.
4.
Hansel MC, Gramignoli R, Skvorak KJ, Dorko K, Marongiu F, Blake W, Davila J, Strom SC: The history and use of human hepatocytes for the treatment of liver diseases: the first 100 patients. Curr Protoc Toxicol 2014;62:14.12.1-14.12.23.
5.
Fox IJ, Chowdhury JR, Kaufman SS, Goertzen TC, Chowdhury NR, Warkentin PI, Dorko K, Sauter BV, Strom SC: Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantation. N Engl J Med 1998;338:1422-1426.
6.
Fisher RA, Strom SC: Human hepatocyte transplantation: worldwide results. Transplantation 2006;82:441-449.
7.
Bilir BM, Guinette D, Karrer F, Kumpe DA, Krysl J, Stephens J, McGavran L, Ostrowska A, Durham J: Hepatocyte transplantation in acute liver failure. Liver Transpl 2000;6:32-40.
8.
Soriano H, Superina R, Ferry GD, Wang LJ, Alonso E, Almond S, Wood RP, Whitington PF: Hepatocyte transplantation (HTX) in children with liver failure (abstract). Hepatology 2001;34:250A.
9.
Darwish AA, Sokal E, Stephenne X, Najimi M, de Goyet Jde V, Reding R: Permanent access to the portal system for cellular transplantation using an implantable port device. Liver Transpl 2004;10:1213-1215.
10.
Stephenne X, Debray FG, Smets F, Jazouli N, Sana G, Tondreau T, Menten R, Goffette P, Boemer F, Schoos R, Gersting SW, Najimi M, Muntau AC, Goyens P, Sokal EM: Hepatocyte transplantation using the domino concept in a child with tetrabiopterin nonresponsive phenylketonuria. Cell Transplant 2012;21:2765-2770.
11.
Ambrosino G, Varotto S, Strom SC, Guariso G, Franchin E, Miotto D, Caenazzo L, Basso S, Carraro P, Valente ML, D'Amico D, Zancan L, D'Antiga L: Isolated hepatocyte transplantation for Crigler-Najjar syndrome type 1. Cell Transplant 2005;14:151-157.
12.
Schneider A, Attaran M, Meier PN, Strassburg C, Manns MP, Ott M, Barthold M, Arseniev L, Becker T, Panning B: Hepatocyte transplantation in an acute liver failure due to mushroom poisoning. Transplantation 2006;82:1115-1116.
13.
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;68:457-460.
14.
Dhawan A, Mitry RR, Hughes RD, Lehec S, Terry C, Bansal S, Arya R, Wade JJ, Verma A, Heaton ND, Rela M, Mieli-Vergani G: Hepatocyte transplantation for inherited factor VII deficiency. Transplantation 2004;78:1812-1814.
15.
Mito M, Kusano M, Kawaura Y: Hepatocyte transplantation in man. Transplant Proc 1992;24:3052-3053.
16.
Strom SC, Chowdhury JR, Fox IJ: Hepatocyte transplantation for the treatment of human disease. Semin Liver Dis 1999;19:39-48.
17.
Gridelli B, Vizzini G, Pietrosi G, Luca A, Spada M, Gruttadauria S, Cintorino D, Amico G, Chinnici C, Miki T, Schmelzer E, Conaldi PG, Triolo F, Gerlach JC: Efficient human fetal liver cell isolation protocol based on vascular perfusion for liver cell-based therapy and case report on cell transplantation. Liver Transpl 2012;18:226-237.
18.
Habibullah CM, Syed IH, Qamar A, Taher-Uz Z: Human fetal hepatocyte transplantation in patients with fulminant hepatic failure. Transplantation 1994;58:951-952.
19.
Grossman M, Raper SE, Kozarsky K, Stein EA, Engelhardt JF, Muller D, Lupien PJ, Wilson JM: Successful ex vivo gene therapy directed to liver in a patient with familial hypercholesterolaemia. Nat Genet 1994;6:335-341.
20.
Muraca M, Gerunda G, Neri D, Vilei MT, Granato A, Feltracco P, Meroni M, Giron G, Burlina AB: hepatocyte transplantation as a treatment for glycogen storage disease type 1a. Lancet 2002;359:317-318.
21.
Sokal EM, Smets F, Bourgois A, Van Maldergem L, Buts JP, Reding R, Bernard Otte J, Evrard V, Latinne D, Vincent MF, Moser A, Soriano HE: Hepatocyte transplantation in a 4-year-old girl with peroxisomal biogenesis disease: technique, safety, and metabolic follow-up. Transplantation 2003;76:735-738.
22.
Mitry RR, Dhawan A, Hughes RD, Bansal S, Lehec S, Terry C, Heaton ND, Karani JB, Mieli-Vergani G, Rela M: One liver, three recipients: segment IV from split-liver procedures as a source of hepatocytes for cell transplantation. Transplantation 2004;77:1614-1616.
23.
Stephenne X, Najimi M, Sibille C, Nassogne MC, Smets F, Sokal EM: Sustained engraftment and tissue enzyme activity after liver cell transplantation for argininosuccinate lyase deficiency. Gastroenterology 2006;130:1317-1323.
24.
Lee KW, Lee JH, Shin SW, Kim SJ, Joh JW, Lee DH, Kim JW, Park HY, Lee SY, Lee HH, Park JW, Kim SY, Yoon HH, Jung DH, Choe YH, Lee SK: Hepatocyte transplantation for glycogen storage disease type Ib. Cell Transplant 2007;16:629-637.
25.
Allen KJ, Mifsud NA, Williamson R, Bertolino P, Hardikar W: Cell-mediated rejection results in allograft loss after liver cell transplantation. Liver Transpl 2008;14:688-694.
26.
Puppi J, Tan N, Mitry RR, Hughes RD, Lehec S, Mieli-Vergani G, Karani J, Champion MP, Heaton N, Mohamed R, Dhawan A: Hepatocyte transplantation followed by auxiliary liver transplantation - a novel treatment for ornithine transcarbamylase deficiency. Am J Transplant 2008;8:452-457.
27.
Li ZR, Mao XH, Hu XX, Nie SD, Shi YZ, Xiang H, Yang JH, Cao OD: Primary human hepatocyte transplantation in the therapy of hepatic failure: 2 cases report. Asian Pac J Trop Med 2012;5:165-168.
28.
Beck BB, Habbig S, Dittrich K, Stippel D, Kaul I, Koerber F, Goebel H, Salido EC, Kemper M, Meyburg J, Hoppe B: Liver cell transplantation in severe infantile oxalosis - a potential bridging procedure to orthotopic liver transplantation? Nephrol Dial Transplant 2012;27:2984-2989.
29.
Ribes-Koninckx C, Pareja Ibars E, Agrasot MA, Bonora-Centelles A, Polo Miquel B, Vila Carbo JJ, Donat Aliaga E, Mir Pallardo J, Gomez-Lechon MJ, Castell JV: Clinical outcome of hepatocyte transplantation in four pediatric patients with inherited metabolic diseases. Cell Transplant 2012;21:2267-2282.
30.
Puppi J, Strom SC, Hughes RD, Bansal S, Castell JV, Dagher I, Ellis EC, Nowak G, Ericzon BG, Fox IJ, Gomez-Lechon MJ, Guha C, Gupta S, Mitry RR, Ohashi K, Ott M, Reid LM, Roy-Chowdhury J, Sokal E, Weber A, Dhawan A: Improving the techniques for human hepatocyte transplantation: report from a consensus meeting in London. Cell Transplant 2012;21:1-10.
31.
Soltys KA, Soto-Gutierrez A, Nagaya M, Baskin KM, Deutsch M, Ito R, Shneider BL, Squires R, Vockley J, Guha C, Roy-Chowdhury J, Strom SC, Platt JL, Fox IJ: Barriers to the successful treatment of liver disease by hepatocyte transplantation. J Hepatol 2010;53:769-774.
32.
Jorns C, Ellis EC, Nowak G, Fischler B, Nemeth A, Strom SC, Ericzon BG: Hepatocyte transplantation for inherited metabolic diseases of the liver. J Intern Med 2012;272:201-223.
33.
Marsman WA, Wiesner RH, Rodriguez L, Batts KP, Porayko MK, Hay JE, Gores GJ, Krom RA: Use of fatty donor liver is associated with diminished early patient and graft survival. Transplantation 1996;62:1246-1251.
34.
Tolosa L, Bonora-Centelles A, Teresa Donato M, Pareja E, Negro A, López S, Castell JV, José Gómez-Lechón M: Steatotic liver: a suitable source for the isolation of hepatic progenitor cells. Liver Int 2011;31:1231-1238.
35.
Fisher RA, Bu D, Thompson M, Tisnado J, Prasad U, Sterling R, Posner M, Strom S: Defining hepatocellular chimerism in a liver failure patient bridged with hepatocyte infusion. Transplantation 2000;69:303-307.
36.
Gramignoli R, Tahan V, Dorko K, Skvorak KJ, Hansel MC, Zhao W, Venkataramanan R, Ellis EC, Jorns C, Ericzon BG, Rosenborg S, Kuiper R, Soltys KA, Mazariegos GV, Fox IJ, Wilson EM, Grompe M, Strom SC: New potential cell source for hepatocyte transplantation: discarded livers from metabolic disease liver transplants. Stem Cell Res 2013;11:563-573.
37.
Mitry RR, Hughes RD, Aw MM, Terry C, Mieli-Vergani G, Girlanda R, Muiesan P, Rela M, Heaton ND, Dhawan A: Human hepatocyte isolation and relationship of cell viability to early graft function. Cell Transplant 2003;12:69-74.
38.
Hughes RD, Mitry RR, Dhawan A, Lehec SC, Girlanda R, Rela M, Heaton ND, Muiesan P: Isolation of hepatocytes from livers from non-heart-beating donors for cell transplantation. Liver Transpl 2006;12:713-717.
39.
Porretti L, Gatti S, Gramignoli R, Colombo F, Lopa R, Cattaneo A, Scalamogna M, Colombo G, Rossi G, Bonino F, Rebulla P, Prati D: Animal model for liver cell banking from non-heart beating donors after prolonged ischaemia time. Dig Liver Dis 2006;38:905-911.
40.
Tolosa L, Pareja-Ibars E, Donato MT, Cortés M, López S, Jiménez N, Mir J, Castell JV, Gómez-Lechón MJ: Neonatal livers: a source for the isolation of good-performing hepatocytes for cell transplantation. Cell Transplant 2013;23:1229-1242.
41.
Khan AA, Shaik MV, Parveen N, Rajendraprasad A, Aleem MA, Habeeb MA, Srinivas G, Raj TA, Tiwari SK, Kumaresan K, Venkateswarlu J, Pande G, Habibullah CM: Human fetal liver-derived stem cell transplantation as supportive modality in the management of end-stage decompensated liver cirrhosis. Cell Transplant 2010;19:409-418.
42.
Howard RB, Christensen AK, Gibbs FA, Pesch LA: The enzymatic preparation of isolated intact parenchymal cells from rat liver. J Cell Biol 1967;35:675-684.
43.
Berry MN, Friend DS: High-yield preparation of isolated rat liver parenchymal cells: a biochemical and fine structural study. J Cell Biol 1969;43:506-520.
44.
Seglen PO: Preparation of isolated rat liver cells. Methods Cell Biol 1976;13:29-83.
45.
Strom SC, Jirtle RL, Jones RS, Novicki DL, Rosenberg MR, Novotny A, Irons G, McLain JR, Michalopoulos G: Isolation, culture, and transplantation of human hepatocytes. J Natl Cancer Inst 1982;68:771-778.
46.
Dorko K, Freeswick PD, Bartoli F, Cicalese L, Bardsley BA, Tzakis A, Nussler AK: A new technique for isolating and culturing human hepatocytes from whole or split livers not used for transplantation. Cell Transplant 1994;3:387-395.
47.
Lee SM, Schelcher C, Demmel M, Hauner M, Thasler WE: Isolation of human hepatocytes by a two-step collagenase perfusion procedure. J Vis Exp DOI: 10.3791/50615.
48.
Alexandrova K, Griesel C, Barthold M, Heuft HG, Ott M, Winkler M, Schrem H, Manns MP, Bredehorn T, Net M, Vidal MM, Kafert-Kasting S, Arseniev L: Large-scale isolation of human hepatocytes for therapeutic application. Cell Transplant 2005;14:845-853.
49.
Gramignoli R, Green ML, Tahan V, Dorko K, Skvorak KJ, Marongiu F, Zao W, Venkataramanan R, Ellis EC, Geller D, Breite AG, Dwulet FE, McCarthy RC, Strom SC: Development and application of purified tissue dissociation enzyme mixtures for human hepatocyte isolation. Cell Transplant 2012;21:1245-1260.
50.
Nakazawa F, Cai H, Miki T, Dorko K, Abdelmeguid A, Walldorf J, Lehmann T, Strom S: Human hepatocyte isolation from cadaver donor liver; in Gupta S, Jansen PLM, Klempnauer J, Manns MP (eds): Falk Symposium 126:Hepatocyte Transplantation. Lancaster, Kouwer Academic Publishers, 2002, vol 126, pp 147-158.
51.
Strom S, Dorko K, Thompson M, Pisarov L, Nussler A: Large scale isolation and culture of human hepatocyte; in Franco D, Doudjema K, Varet K (eds): Ilots de Langerhans et hépatocytes: vers une utilisation thérapeutique. Les Editions INSERM, 1998, pp 195-206.
52.
Strom S, Fisher R: Hepatocyte transplantation: new possibilities for therapy. Gastroenterology 2003;124:568-571.
53.
Gramignoli R, Tahan V, Dorko K, Venkataramanan R, Fox IJ, Ellis EC, Vosough M, Strom SC: Rapid-and-sensitive assessment of human hepatocyte functions. Cell Transplant 2014;23:1545-1556.
54.
Bonora-Centelles A, Donato MT, Lahoz A, Pareja E, Mir J, Castell JV, Gómez-Lechón MJ: Functional characterization of hepatocytes for cell transplantation: customized cell preparation for each receptor. Cell Transplant 2010;19:21-28.
55.
Jorns C, Nemeth A, Nowak G, Zemack H, Mörk LM, Johansson H, Gramignoli R, Fischler B, Strom S, Ellis ECS, Ericzon BG: Hepatocyte transplantation combined with partial liver resection preconditioning in patients with Crigler-Najjar type I (abstract). Hepatology 2013;58:95A.
56.
Pless G, Sauer IM, Rauen U: Improvement of the cold storage of isolated human hepatocytes. Cell Transplant 2012;21:23-37.
57.
Meyburg J, Hoffmann GF: Liver, liver cell and stem cell transplantation for the treatment of urea cycle defects. Mol Genet Metab 2010;100(suppl 1):S77-S83.
58.
Meyburg J, Das AM, Hoerster F, Lindner M, Kriegbaum H, Engelmann G, Schmidt J, Ott M, Pettenazzo A, Luecke T, Bertram H, Hoffmann GF, Burlina A: One liver for four children: first clinical series of liver cell transplantation for severe neonatal urea cycle defects. Transplantation 2009;87:636-641.
59.
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 USA 1995;92:5860-5864.
60.
Gupta S, Rajvanshi P, Sokhi R, Slehria S, Yam A, Kerr A, Novikoff PM: Entry and integration of transplanted hepatocytes in rat liver plates occur by disruption of hepatic sinusoidal endothelium. Hepatology 1999;29:509-519.
61.
Quaglia A, Lehec SC, Hughes RD, Mitry RR, Knisely AS, Devereaux S, Richards J, Rela M, Heaton ND, Portmann BC, Dhawan A: Liver after hepatocyte transplantation for liver-based metabolic disorders in children. Cell Transplant 2008;17:1403-1414.
62.
Bohnen NI, Charron M, Reyes J, Rubinstein W, Strom SC, Swanson D, Towbin R: Use of indium-111-labeled hepatocytes to determine the biodistribution of transplanted hepatocytes through portal vein infusion. Clin Nucl Med 2000;25:447-450.
63.
Nagata H, Ito M, Shirota C, Edge A, McCowan TC, Fox IJ: Route of hepatocyte delivery affects hepatocyte engraftment in the spleen. Transplantation 2003;76:732-734.
64.
Ohashi K, Waugh JM, Dake MD, Yokoyama T, Kuge H, Nakajima Y, Yamanouchi M, Naka H, Yoshioka A, Kay MA: Liver tissue engineering at extrahepatic sites in mice as a potential new therapy for genetic liver diseases. Hepatology 2005;41:132-140.
65.
Uyama S, Kaufmann PM, Kneser U, Fiegel HC, Pollok JM, Kluth D, Vacanti JP, Rogiers X: Hepatocyte transplantation using biodegradable matrices in ascorbic acid-deficient rats: comparison with heterotopically transplanted liver grafts. Transplantation 2001;71:1226-1231.
66.
Komori J, Deward AD, Gramignoli R, Strom SC, Fontes P, Lagasse E: Potential barriers to human hepatocyte transplantation in MUP-uPA(tg(+/+))Rag2(-/-)γC(-/-) mice. Cell Transplant 2014;23:1537-1544.
67.
Tatsumi K, Ohashi K, Shima M, Nakajima Y, Okano T, Yoshioka A: Therapeutic effects of hepatocyte transplantation on hemophilia B. Transplantation 2008;86:167-170.
68.
Kalayoglu M, Sollinger HW, Stratta RJ, D'Alessandro AM, Hoffmann RM, Pirsch JD, Belzer FO: Extended preservation of the liver for clinical transplantation. Lancet 1988;1:617-619.
69.
Belzer FO, Southard JH: Principles of solid-organ preservation by cold storage. Transplantation 1988;45:673-676.
70.
Dondero F, Paugam-Burtz C, Danjou F, Stocco J, Durand F, Belghiti J: A randomized study comparing IGL-1 to the University of Wisconsin preservation solution in liver transplantation. Ann Transplant 2010;15:7-14.
71.
Abrahamse SL, van Runnard Heimel P, Hartman RJ, Chamuleau RA, van Gulik TM: Induction of necrosis and DNA fragmentation during hypothermic preservation of hepatocytes in UW, HTK, and Celsior solutions. Cell Transplant 2003;12:59-68.
72.
Gramignoli R, Dorko K, Tahan V, Skvorak KJ, Ellis E, Jorns C, Ericzon BG, Fox IJ, Strom SC: Hypothermic storage of human hepatocytes for transplantation. Cell Transplant 2013;23:1143-1151.
73.
Smets FN, Chen Y, Wang LJ, Soriano HE: Loss of cell anchorage triggers apoptosis (anoikis) in primary mouse hepatocytes. Mol Genet Metab 2002;75:344-352.
74.
Jorns C, Gramignoli R, Saliem M, Zemack H, Mork LM, Isaksson B, Nowak G, Ericzon BG, Strom S, Ellis E: Strategies for short-term storage of hepatocytes for repeated clinical infusions. Cell Transplant 2013;23:1009-1018.
75.
Allen KJ, Soriano HE: Liver cell transplantation: the road to clinical application. J Lab Clin Med 2001;138:298-312.
76.
Slehria S, Rajvanshi P, Ito Y, Sokhi RP, Bhargava KK, Palestro CJ, McCuskey RS, Gupta S: Hepatic sinusoidal vasodilators improve transplanted cell engraftment and ameliorate microcirculatory perturbations in the liver. Hepatology 2002;35:1320-1328.
77.
Kim KS, Joseph B, Inada M, Gupta S: Regulation of hepatocyte engraftment and proliferation after cytotoxic drug-induced perturbation of the rat liver. Transplantation 2005;80:653-659.
78.
Malhi H, Annamaneni P, Slehria S, Joseph B, Bhargava KK, Palestro CJ, Novikoff PM, Gupta S: Cyclophosphamide disrupts hepatic sinusoidal endothelium and improves transplanted cell engraftment in rat liver. Hepatology 2002;36:112-121.
79.
Joseph B, Malhi H, Bhargava KK, Palestro CJ, McCuskey RS, Gupta S: Kupffer cells participate in early clearance of syngeneic hepatocytes transplanted in the rat liver. Gastroenterology 2002;123:1677-1685.
80.
Azuma H, Paulk N, Ranade A, Dorrell C, Al-Dhalimy M, Ellis E, Strom S, Kay MA, Finegold M, Grompe M: Robust expansion of human hepatocytes in Fah-/-/Rag2-/-/Il2rg-/- mice. Nat Biotechnol 2007;25:903-910.
81.
Overturf K, al-Dhalimy M, Ou CN, Finegold M, Grompe M: Serial transplantation reveals the stem-cell-like regenerative potential of adult mouse hepatocytes. Am J Pathol 1997;151:1273-1280.
82.
Laconi E, Oren R, Mukhopadhyay DK, Hurston E, Laconi S, Pani P, Dabeva MD, Shafritz DA: Long-term, near-total liver replacement by transplantation of isolated hepatocytes in rats treated with retrorsine. Am J Pathol 1998;153:319-329.
83.
Mignon A, Guidotti JE, Mitchell C, Fabre M, Wernet A, De La Coste A, Soubrane O, Gilgenkrantz H, Kahn A: Selective repopulation of normal mouse liver by Fas/CD95-resistant hepatocytes. Nat Med 1998;4:1185-1188.
84.
Guha C, Yamanouchi K, Jiang J, Wang X, Roy Chowdhury N, Santana A, Shapiro LJ, Salido E, Roy-Chowdhury J: Feasibility of hepatocyte transplantation-based therapies for primary hyperoxalurias. Am J Nephrol 2005;25:161-170.
85.
Joseph B, Kumaran V, Berishvili E, Bhargava KK, Palestro CJ, Gupta S: Monocrotaline promotes transplanted cell engraftment and advances liver repopulation in rats via liver conditioning. Hepatology 2006;44:1411-1420.
86.
Rhim JA, Sandgren EP, Palmiter RD, Brinster RL: Complete reconstitution of mouse liver with xenogeneic hepatocytes. Proc Natl Acad Sci USA 1995;92:4942-4946.
87.
Grompe M, Laconi E, Shafritz DA: Principles of therapeutic liver repopulation. Semin Liver Dis 1999;19:7-14.
88.
Koenig S, Krause P, Schmidt TK, Rave-Fraenk M, Rothe H, Hermann RM, Becker H, Hess CF, Christiansen H: Irradiation as preparative regimen for hepatocyte transplantation causes prolonged cell cycle block. Int J Radiat Biol 2008;84:285-298.
89.
Malhi H, Gorla GR, Irani AN, Annamaneni P, Gupta S: Cell transplantation after oxidative hepatic preconditioning with radiation and ischemia-reperfusion leads to extensive liver repopulation. Proc Natl Acad Sci USA 2002;99:13114-13119.
90.
Michalopoulos GK: Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas. Am J Pathol 2010;176:2-13.
91.
Grossman M, Raper SE, Wilson JM: Transplantation of genetically modified autologous hepatocytes into nonhuman primates: feasibility and short-term toxicity. Hum Gene Ther 1992;3:501-510.
92.
Sigal SH, Rajvanshi P, Gorla GR, Sokhi RP, Saxena R, Gebhard DR Jr, Reid LM, Gupta S: Partial hepatectomy-induced polyploidy attenuates hepatocyte replication and activates cell aging events. Am J Physiol 1999;276:G1260-G1272.
93.
Abdalla EK: Portal vein embolization (prior to major hepatectomy) effects on regeneration, resectability, and outcome. J Surg Oncol 2010;102:960-967.
94.
Rous P, Larimore LD: Relation of the portal blood to liver maintenance: a demonstration of liver atrophy conditional on compensation. J Exp Med 1920;31:609-632.
95.
Furrer K, Tian Y, Pfammatter T, Jochum W, El-Badry AM, Graf R, Clavien PA: Selective portal vein embolization and ligation trigger different regenerative responses in the rat liver. Hepatology 2008;47:1615-1623.
96.
de Santibañes E, Clavien PA. Playing Play-Doh to prevent postoperative liver failure: the ‘ALPPS' approach. Ann Surg 2012;255:415-417.
97.
Zhang GQ, Zhang ZW, Lau WY, Chen XP: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): a new strategy to increase resectability in liver surgery. Int J Surg 2014;12:437-441.
98.
Yamanouchi K, Zhou H, Roy-Chowdhury N, Macaluso F, Liu L, Yamamoto T, Yannam GR, Enke C, Solberg TD, Adelson AB, Platt JL, Fox IJ, Roy-Chowdhury J, Guha C: Hepatic irradiation augments engraftment of donor cells following hepatocyte transplantation. Hepatology 2009;49:258-267.
99.
Guha C, Sharma A, Gupta S, Alfieri A, Gorla GR, Gagandeep S, Sokhi R, Roy-Chowdhury N, Tanaka KE, Vikram B, Roy-Chowdhury J: Amelioration of radiation-induced liver damage in partially hepatectomized rats by hepatocyte transplantation. Cancer Res 1999;59:5871-5874.
100.
Guha C, Parashar B, Deb NJ, Sharma A, Gorla GR, Alfieri A, Roy-Chowdhury N, Roy-Chowdhury J, Vikram B: Liver irradiation: a potential preparative regimen for hepatocyte transplantation. Int J Radiat Oncol Biol Phys 2001;49:451-457.
101.
Sempoux C, Horsmans Y, Geubel A, Fraikin J, Van Beers BE, Gigot JF, Lerut J, Rahier J: Severe radiation-induced liver disease following localized radiation therapy for biliopancreatic carcinoma: activation of hepatic stellate cells as an early event. Hepatology 1997;26:128-134.
102.
Ramanathan R, Sharma A, Kaspar M, Behnke M, Song S, Stravitz RT, Cotterell A, Posner M, Fisher RA: Local allograft irradiation as an adjunct to treat severe resistant rejection after liver transplantation in adults. Liver Transpl 2014, Epub ahead of print.
103.
Stephenne X, Najimi M, Janssen M, Reding R, de Ville de Goyet J, Sokal EM: Liver allograft radiotherapy to treat rejection in children: efficacy in orthotopic liver transplantation and long-term safety. Liver Int 2005;25:1108-1113.
104.
Nussler A, Konig S, Ott M, Sokal E, Christ B, Thasler W, Brulport M, Gabelein G, Schormann W, Schulze M, Ellis E, Kraemer M, Nocken F, Fleig W, Manns M, Strom SC, Hengstler JG: Present status and perspectives of cell-based therapies for liver diseases. J Hepatol 2006;45:144-159.
105.
Lainas P, Boudechiche L, Osorio A, Coulomb A, Weber A, Pariente D, Franco D, Dagher I: Liver regeneration and recanalization time course following reversible portal vein embolization. J Hepatol 2008;49:354-362.
106.
Mas VR, Maluf DG, Thompson M, Ferreira-Gonzalez A, Fisher RA: Engraftment measurement in human liver tissue after liver cell transplantation by short tandem repeats analysis. Cell Transplant 2004;13:231-236.
107.
Modo M: Noninvasive imaging of transplanted cells. Curr Opin Organ Transplant 2008;13:654-658.
108.
Bulte JW, Kraitchman DL: Iron oxide MR contrast agents for molecular and cellular imaging. NMR Biomed 2004;17:484-499.
109.
Puppi J, Modo M: Use of magnetic resonance imaging contrast agents to detect transplanted liver cells. Top Magn Reson Imaging 2009;20:113-120.
110.
Inomata Y, Tanaka K, Okajima H, Uemoto S, Ozaki N, Egawa H, Satomura K, Kiuchi T, Yamaoka Y: Living related liver transplantation for children younger than one year old. Eur J Pediatr Surg 1996;6:148-151.
111.
Dhawan A, Puppi J, Hughes RD, Mitry RR: Human hepatocyte transplantation: current experience and future challenges. Nat Rev Gastroenterol Hepatol 2010;7:288-298.
112.
Francavilla A, Starzl TE, Barone M, Zeng QH, Porter KA, Zeevi A, Markus PM, van den Brink MR, Todo S: Studies on mechanisms of augmentation of liver regeneration by cyclosporine and FK 506. Hepatology 1991;14:140-143.
113.
Herrera MB, Bruno S, Buttiglieri S, Tetta C, Gatti S, Deregibus MC, Bussolati B, Camussi G: Isolation and characterization of a stem cell population from adult human liver. Stem Cells 2006;24:2840-2850.
114.
Herrera MB, Fonsato V, Bruno S, Grange C, Gilbo N, Romagnoli R, Tetta C, Camussi G: Human liver stem cells improve liver injury in a model of fulminant liver failure. Hepatology 2013;57:311-319.
115.
Schaub JR, Malato Y, Gormond C, Willenbring H: Evidence against a stem cell origin of new hepatocytes in a common mouse model of chronic liver injury. Cell Rep 2014;8:933-939.
116.
Yanger K, Knigin D, Zong Y, Maggs L, Gu G, Akiyama H, Pikarsky E, Stanger BZ: Adult hepatocytes are generated by self-duplication rather than stem cell differentiation. Cell Stem Cell 2014;15:340-349.
117.
Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S: Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007;131:861-872.
118.
Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin, II, Thomson JA: Induced pluripotent stem cell lines derived from human somatic cells. Science 2007;318:1917-1920.
119.
Rashid ST, Corbineau S, Hannan N, Marciniak SJ, Miranda E, Alexander G, Huang-Doran I, Griffin J, Ahrlund-Richter L, Skepper J, Semple R, Weber A, Lomas DA, Vallier L: Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells. J Clin Invest 2010;120:3127-3136.
120.
Hansel MC, Gramignoli R, Blake W, Davila J, Skvorak K, Dorko K, Tahan V, Lee BR, Tafaleng E, Guzman-Lepe J, Soto-Gutierrez A, Fox IJ, Strom SC: Increased reprogramming of human fetal hepatocytes compared with adult hepatocytes in feeder-free conditions. Cell Transplant 2013;23:27-38.
121.
Campard D, Lysy PA, Najimi M, Sokal EM: Native umbilical cord matrix stem cells express hepatic markers and differentiate into hepatocyte-like cells. Gastroenterology 2008;134:833-848.
122.
Si-Tayeb K, Noto FK, Nagaoka M, Li J, Battle MA, Duris C, North PE, Dalton S, Duncan SA: Highly efficient generation of human hepatocyte-like cells from induced pluripotent stem cells. Hepatology 2010;51:297-305.
123.
Miki T, Lehmann T, Cai H, Stolz DB, Strom SC: Stem cell characteristics of amniotic epithelial cells. Stem Cells 2005;23:1549-1559.
124.
Marongiu F, Gramignoli R, Dorko K, Miki T, Ranade AR, Paola Serra M, Doratiotto S, Sini M, Sharma S, Mitamura K, Sellaro TL, Tahan V, Skvorak KJ, Ellis EC, Badylak SF, Davila JC, Hines R, Laconi E, Strom SC: Hepatic differentiation of amniotic epithelial cells. Hepatology 2011;53:1719-1729.
125.
Skvorak KJ, Dorko K, Marongiu F, Tahan V, Hansel MC, Gramignoli R, Arning E, Bottiglieri T, Gibson KM, Strom SC: Improved amino acid, bioenergetic metabolite and neurotransmitter profiles following human amnion epithelial cell transplant in intermediate maple syrup urine disease mice. Mol Genet Metab 2013;109:132-138.
126.
Skvorak KJ, Dorko K, Marongiu F, Tahan V, Hansel MC, Gramignoli R, Gibson KM, Strom SC: Placental stem cell correction of murine intermediate maple syrup urine disease. Hepatology 2013;57:1017-1023.
127.
Strom SC, Skvorak K, Gramignoli R, Marongiu F, Miki T: Translation of amnion stem cells to the clinic. Stem Cells Dev 2013;22(suppl 1):96-102.
© 2015 S. Karger AG, Basel
2015
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.