Competency of different cell models to predict human hepatotoxic drugs

Expert Opinion on Drug Metabolism and Toxicology

Volumn 10, Issue 11, 2014, Pages 1553-1568

  Gómez Lechón, M José ^a,b   Tolosa, Laia ^a   Conde, Isabel ^a   Donato, M Teresa ^a,b,c  

^a INSTITUTO DE INVESTIGACIÓN SANITARIA DEL HOSPITAL CLÍNICO SAN CARLOS IDISSC   (Spain)

^b INSTITUTO DE SALUD CARLOS III   (Spain)

^c UNIVERSITY OF VALENCIA   (Spain)

Author keywords

Co culture; CYP engineered cell line; Hepatocytes; Hepatoma cell line; Microfluidic device; Sandwich culture; Scaffold based culture; Spheroids

Indexed keywords

COLLAGEN; DRUG; DRUG METABOLIZING ENZYME;

CELL ENGINEERING; CELL LINE; COCULTURE; DRUG METABOLISM; EMBRYONIC STEM CELL; HEPARG CELL; HEPATOCELLULAR CARCINOMA CELL LINE; HEPG2 CELL LINE; HUMAN; HUMAN CELL; LIVER CELL; LIVER CELL CULTURE; LIVER TOXICITY; MICROFLUIDICS; MULTICELLULAR SPHEROID; PLURIPOTENT STEM CELL; PROTEIN EXPRESSION; REVIEW; RISK ASSESSMENT; ANIMAL; CELL CULTURE; CYTOLOGY; DRUG EFFECTS; LIVER; PATHOLOGY; PATHOPHYSIOLOGY; PROCEDURES; TOXIC HEPATITIS; TOXICITY TESTING; TUMOR CELL LINE;

ANIMALS; CELL LINE; CELL LINE, TUMOR; CELLS, CULTURED; DRUG-INDUCED LIVER INJURY; HEPATOCYTES; HUMANS; LIVER; TOXICITY TESTS;

EID: 84911367430     PISSN: 17425255     EISSN: 17447607     Source Type: Journal    
DOI: 10.1517/17425255.2014.967680     Document Type: Review

References (127)

1. Gomez-Lechon MJ, Tolosa L, Castell JV, et al. Mechanism-based selection of compounds for the development of innovative in vitro approaches to hepatotoxicity studies in the LIINTOP project. Toxicol In Vitro 2010;24:1879-89.
2. Bjornsson ES, Bergmann OM, Bjornsson HK, et al. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013;144:1419-25
3. Reuben A, Koch DG, Lee WM. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010;52:2065-76
4. Hadem J, Tacke F, Bruns T, et al. Etiologies and outcomes of acute liver failure in Germany. Clin Gastroenterol Hepatol 2012;10:664-9
5. Norris W, Paredes AH, Lewis JH. Drug-induced liver injury in. 2007. Curr Opin Gastroenterol 2008;24:287-97
6. Lewis DF, Ioannides C, Parke DV. Cytochromes P450 and species differences in xenobiotic metabolism and activation of carcinogen. Environ Health Perspect 1998;106:633-41
7. O'Brien PJ, Chan K, Silber PM. Human and animal hepatocytes in vitro with extrapolation in vivo. Chem Biol Interact 2004;150:97-114.
8. Godoy P, Hewitt NJ, Albrecht U, et al. Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME. Arch Toxicol 2013;87:1315-530.
9. O'Brien PJ, Irwin W, Diaz D, et al. High concordance of drug-induced human hepatotoxicity with in vitro cytotoxicity measured in a novel cell-based model using high content screening. Arch Toxicol 2006;80:580-604
10. Soldatow VY, Lecluyse EL, Griffith LG, et al. Models for liver toxicity testing. Toxicol Res (Camb) 2013;2:23-39.
11. Gomez-Lechon MJ, Castell JV, Donato MT. An update on metabolism studies using human hepatocytes in primary culture. Expert Opin Drug Metab Toxicol 2008;4:837-54
12. Gomez-Lechon MJ, Donato MT, Castell JV, et al. Human hepatocytes as a tool for studying toxicity and drug metabolism. Curr Drug Metab 2003;4:292-312
13. Gomez-Lechon MJ, Donato MT, Castell JV, et al. Human hepatocytes in primary culture: the choice to investigate drug metabolism in man. Curr Drug Metab 2004;5:443-62
14. Hewitt NJ, Gómez-Lechon MJ, Houston JB, et al. Primary hepatocytes: current understanding of the regulation of metabolic enzymes and transporter proteins, and pharmaceutical practice for the use of hepatocytes in metabolism, enzyme induction, transporter, clearance, and hepatotoxicity studies. Drug Metab Rev 2007;39:159-234.
15. LeCluyse EL. Human hepatocyte culture systems for the in vitro evaluation of cytochrome P450 expression and regulation. Eur J Pharm Sci 2001;13:343-68
16. Terry C, Hughes RD, Mitry RR, et al. Cryopreservation-induced nonattachment of human hepatocytes: role of adhesion molecules. Cell Transplant 2007;16:639-47
17. Donato MT, Lahoz A, Montero S, et al. Functional assessment of the quality of human hepatocyte preparations for cell transplantation. Cell Transplant 2008;17:1211-19
18. Tolosa L, Bonora-Centelles A, Donato MT, et al. Influence of platelet lysate on the recovery and metabolic performance of cryopreserved human hepatocytes upon thawing. Transplantation 2011;91:1340-6
19. Li AP, Lu C, Brent JA, et al. Cryopreserved human hepatocytes: characterization of drug-metabolizing enzyme activities and applications in higher throughput screening assays for hepatotoxicity, metabolic stability, and drug-drug interaction potential. Chem Biol Interact 1999;121:17-35
20. McGinnity DF, Soars MG, Urbanowicz RA, et al. Evaluation of fresh and cryopreserved hepatocytes as in vitro drug metabolism tools for the prediction of metabolic clearance. Drug Metab Dispos 2004;32:1247-53
21. Alexandre E, Baze A, Parmentier C, et al. Plateable cryopreserved human hepatocytes for the assessment of cytochrome P450 inducibility: experimental condition-related variables affecting their response to inducers. Xenobiotica 2012;42:968-79
22. Kim HM, Han SB, Hyun BH, et al. Functional human hepatocytes: isolation from small liver biopsy samples and primary cultivation with liver-specific functions. J Toxicol Sci 1995;20:565-78
23. Olinga P, Merema M, Sandker GW, et al. Uptake of taurocholic acid in human hepatocytes isolated from livers of donors of different age. J Pediatr Gastroenterol Nutr 1998;27:366-8
24. Meng Q. Three-dimensional culture of hepatocytes for prediction of drug-induced hepatotoxicity. Expert Opin Drug Metab Toxicol 2010;6:733-46
25. Kienhuis AS, Wortelboer HM, Maas WJ, et al. A sandwich-cultured rat hepatocyte system with increased metabolic competence evaluated by gene expression profiling. Toxicol In Vitro 2007;21:892-901
26. Rowe C, Goldring CE, Kitteringham NR, et al. Network analysis of primary hepatocyte dedifferentiation using a shotgun proteomics approach. J Proteome Res 2010;9:2658-68
27. Trauner M, Boyer JL. Bile salt transporters: molecular characterization, function, and regulation. Physiol Rev 2003;83:633-71
28. Guo C, He L, Yao D, et al. Alpha-naphthylisothiocyanate modulates hepatobiliary transporters in sandwich-cultured rat hepatocytes. Toxicol Lett 2014;224:93-100
29. Kotani N, Maeda K, Watanabe T, et al. Culture period-dependent changes in the uptake of transporter substrates in sandwich-cultured rat and human hepatocytes. Drug Metab Dispos 2011;39:1503-10
30. Chatterjee S, Richert L, Augustijns P, et al. Hepatocyte-based in vitro model for assessment of drug-induced cholestasis. Toxicol Appl Pharmacol 2014;274:124-36
31. De Bruyn T, Chatterjee S, Fattah S, et al. Sandwich-cultured hepatocytes: utility for in vitro exploration of hepatobiliary drug disposition and drug-induced hepatotoxicity. Expert Opin Drug Metab Toxicol 2013;9:589-616
32. Lepist EI, Gillies H, Smith W, et al. Evaluation of the endothelin receptor antagonists ambrisentan, bosentan, macitentan, and sitaxsentan as hepatobiliary transporter inhibitors and substrates in sandwich-cultured human hepatocytes. PLoS One 2014;9:e87548
33. Marion TL, Perry CH, St Claire RL, et al. Endogenous bile acid disposition in rat and human sandwich-cultured hepatocytes. Toxicol Appl Pharmacol 2012;261:1-9
34. Mueller D, Heinzle E, Noor F. 3D hepatic in vitro models as tools for toxicity studies. Current Tissue Eng 2013;2:78-89.
35. Lau TT, Lee LQ, Leong W, et al. Formation of model hepatocellular aggregates in a hydrogel scaffold using degradable genipin crosslinked gelatin microspheres as cell carriers. Biomed Mater 2012;7:065003
36. De Kock J, Ceelen L, De Spiegelaere W, et al. Simple and quick method for whole-liver decellularization: a novel in vitro three-dimensional bioengineering tool? Arch Toxicol 2011;85:607-12
37. Kim BS, Park IK, Hoshiba T, et al. Design of artificial extracellular matrices for tissue engineering. Prog Polym Sci 2011;36:238-68
38. Cho CS, Seo SJ, Park IK, et al. Galactose-carrying polymers as extracellular matrices for liver tissue engineering. Biomaterials 2006;27:576-85
39. Knight E, Murray B, Carnachan R, et al. Alvetex(R): polystyrene scaffold technology for routine three dimensional cell culture. Methods Mol Biol 2011;695:323-40
40. Burkard A, Dahn C, Heinz S, et al. Generation of proliferating human hepatocytes using Upcyte(R) technology: characterisation and applications in induction and cytotoxicity assays. Xenobiotica 2012;42:939-56
41. Tania M, Hsu MN, Png SN, et al. Perfusion enhanced polydimethylsiloxane based scaffold cell culturing system for multi-well drug screening platform. Biotechnol Prog 2014;30:418-28
42. van Zijl F, Mikulits W. Hepatospheres: three dimensional cell cultures resemble physiological conditions of the liver. World J Hepatol 2010;2:1-7
43. Lin RZ, Chang HY. Recent advances in three-dimensional multicellular spheroid culture for biomedical research. Biotechnol J 2008;3:1172-84
44. Tostoes RM, Leite SB, Serra M, et al. Human liver cell spheroids in extended perfusion bioreactor culture for repeated-dose drug testing. Hepatology 2012;55:1227-36
45. Schyschka L, Sanchez JJ, Wang Z, et al. Hepatic 3D cultures but not 2D cultures preserve specific transporter activity for acetaminophen-induced hepatotoxicity. Arch Toxicol 2013;87:1581-93
46. Ohkura T, Ohta K, Nagao T, et al. Evaluation of human hepatocytes cultured by three-dimensional spheroid systems for drug metabolism. Drug Metab Pharmacokinet 2014; Epub ahead of print
47. Inamori M, Mizumoto H, Kajiwara T. An approach for formation of vascularized liver tissue by endothelial cell-covered hepatocyte spheroid integration. Tissue Eng Part A 2009;15:2029-37
48. Khetani SR, Bhatia SN. Microscale culture of human liver cells for drug development. Nat Biotechnol 2008;26:120-6
49. No da Y, Lee SA, Choi YY, et al. Functional 3D human primary hepatocyte spheroids made by coculturing hepatocytes from partial hepatectomy specimens and human adipose-derived stem cells. PLoS One 2012;7:e50723
50. Kostadinova R, Boess F, Applegate D, et al. A long-term three dimensional liver co-culture system for improved prediction of clinically relevant drug-induced hepatotoxicity. Toxicol Appl Pharmacol 2013;268:1-16.
51. Sung JH, Choi JR, Kim D, et al. Fluorescence optical detection in situ for real-time monitoring of cytochrome P450 enzymatic activity of liver cells in multiple microfluidic devices. Biotechnol Bioeng 2009;104:516-25
52. Goral VN, Hsieh YC, Petzold ON, et al. Perfusion-based microfluidic device for three-dimensional dynamic primary human hepatocyte cell culture in the absence of biological or synthetic matrices or coagulants. Lab Chip 2010;10:3380-6
53. Chao P, Maguire T, Novik E, et al. Evaluation of a microfluidic based cell culture platform with primary human hepatocytes for the prediction of hepatic clearance in human. Biochem Pharmacol 2009;78:625-32
54. Novik E, Maguire TJ, Chao P, et al. A microfluidic hepatic coculture platform for cell-based drug metabolism studies. Biochem Pharmacol 2010;79:1036-44
55. Bhushan A, Senutovitch N, Bale SS, et al. Towards a three-dimensional microfluidic liver platform for predicting drug efficacy and toxicity in humans. Stem Cell Res Ther 2013;4(Suppl 1):S16
56. Donato MT, Jover R, Gomez-Lechon MJ. Hepatic cell lines for drug hepatotoxicity testing: limitations and strategies to upgrade their metabolic competence by gene engineering. Curr Drug Metab 2013;14:946-68
57. Donato MT, Lahoz A, Castell JV, et al. Cell lines: a tool for in vitro drug metabolism studies. Curr Drug Metab 2008;9:1-11
58. Schoonen WG, Westerink WM, de Roos JA, et al. Cytotoxic effects of 100 reference compounds on Hep G2 and HeLa cells and of 60 compounds on ECC-1 and CHO cells. I mechanistic assays on ROS, glutathione depletion and calcein uptake. Toxicol In Vitro 2005;19:505-16
59. Schoonen WG, Stevenson JC, Westerink WM, et al. Cytotoxic effects of 109 reference compounds on rat H4IIE and human HepG2 hepatocytes. III: mechanistic assays on oxygen consumption with MitoXpress and NAD (P)H production with Alamar Blue. Toxicol In Vitro 2012;26:511-25
60. Van Summeren A, Renes J, Bouwman FG, et al. Proteomics investigations of drug-induced hepatotoxicity in HepG2 cells. Toxicol Sci 2011;120:109-22
61. Jetten MJ, Kleinjans JC, Claessen SM, et al. Baseline and genotoxic compound induced gene expression profiles in HepG2 and HepaRG compared to primary human hepatocytes. Toxicol In Vitro 2013;27:2031-40
62. Van den Hof WF, Coonen ML, van Herwijnen M, et al. Classification of hepatotoxicants using HepG2 cells: a proof of principle study. Chem Res Toxicol 2014;27:433-42
63. Tolosa L, Pinto S, Donato MT, et al. Development of a multiparametric cell-based protocol to screen and classify the hepatotoxicity potential of drugs. Toxicol Sci 2012;127:187-98
64. Garside H, Marcoe KF, Chesnut-Speelman J, et al. Evaluation of the use of imaging parameters for the detection of compound-induced hepatotoxicity in 384-well cultures of HepG2 cells and cryopreserved primary human hepatocytes. Toxicol In Vitro 2014;28:171-81
65. Kanebratt KP, Andersson TB. Evaluation of HepaRG cells as an in vitro model for human drug metabolism studies. Drug Metab Dispos 2008;36:1444-52
66. Guo L, Dial S, Shi L, et al. Similarities and differences in the expression of drugmetabolizing enzymes between human hepatic cell lines and primary human hepatocytes. Drug Metab Dispos 2011;39:528-38.
67. Lan SF, Safiejko-Mroczka B, Starly B. Long-term cultivation of HepG2 liver cells encapsulated in alginate hydrogels: a study of cell viability, morphology and drug metabolism. Toxicol In Vitro 2010;24:1314-23
68. Nakamura K, Kato N, Aizawa K, et al. Expression of albumin and cytochrome P450 enzymes in HepG2 cells cultured with a nanotechnology-based culture plate with microfabricated scaffold. J Toxicol Sci 2011;36(5):625-33
69. Ramaiahgari SC, den Braver MW, Herpers B, et al. A 3D in vitro model of differentiated HepG2 cell spheroids with improved liver-like properties for repeated dose high-throughput toxicity studies. Arch Toxicol 2014;88:1083-95
70. Aritomi K, Ishitsuka Y, Tomishima Y, et al. Evaluation of three-dimensional cultured HepG2 cells in a nano culture plate system: an in vitro human model of acetaminophen hepatotoxicity. J Pharmacol Sci 2014;124:218-29
71. Aninat C, Piton A, Glaise D, et al. Expression of cytochromes P450, conjugating enzymes and nuclear receptors in human hepatoma HepaRG cells. Drug Metab Dispos 2006;34:75-83
72. Le Vee M, Noel G, Jouan E, et al. Polarized expression of drug transporters in differentiated human hepatoma HepaRG cells. Toxicol In Vitro 2013;27:1979-86
73. Rodrigues RM, Bouhifd M, Bories G, et al. Assessment of an automated in vitro basal cytotoxicity test system based on metabolically-competent cells. Toxicol In Vitro 2013;27:760-7
74. Klein S, Mueller D, Schevchenko V, et al. Long-term maintenance of HepaRG cells in serum-free conditions and application in a repeated dose study. J Appl Toxicol 2013;doi: 10.1002/jat.2929
75. McGill MR, Yan HM, Ramachandran A, et al. HepaRG cells: a human model to study mechanisms of acetaminophen hepatotoxicity. Hepatology 2011;53:974-82
76. Antherieu S, Bachour-El Azzi P, Dumont J, et al. Oxidative stress plays a major role in chlorpromazine-induced cholestasis in human HepaRG cells. Hepatology 2013;57:1518-29
77. Landesmann B, Mennecozzi M, Berggren E, et al. Adverse outcome pathway-based screening strategies for an animal-free safety assessment of chemicals. Altern Lab Anim 2013;41:461-71
78. Laurent V, Fraix A, Montier T, et al. Highly efficient gene transfer into hepatocyte-like HepaRG cells: new means for drug metabolism and toxicity studies. Biotechnol J 2010;5:314-20
79. Leite SB, Teixeira AP, Miranda JP, et al. Merging bioreactor technology with 3D hepatocyte-fibroblast culturing approaches: improved in vitro models for toxicological applications. Toxicol In Vitro 2011;25:825-32
80. Mueller D, Kramer L, Hoffmann E, et al. 3D organotypic HepaRG cultures as in vitro model for acute and repeated dose toxicity studies. Toxicol In Vitro 2014;28:104-12
81. Gunness P, Mueller D, Shevchenko V, et al. 3D organotypic cultures of human HepaRG cells: a tool for in vitro toxicity studies. Toxicol Sci 2013;133:67-78
82. Dambach DM, Andrews BA, Moulin F. New technologies and screening strategies for hepatotoxicity: use of in vitro models. Toxicol Pathol 2005;33:17-26.
83. Gustafsson F, Foster AJ, Sarda S, et al. A correlation between the in vitro drug toxicity of drugs to cell lines that express human P450s and their propensity to cause liver injury in humans. Toxicol Sci 2014;137:189-211
84. Greer ML, Barber J, Eakins J, et al. Cell based approaches for evaluation of drug-induced liver injury. Toxicology 2010;268:125-31.
85. Yoshitomi S, Ikemoto K, Takahashi J, et al. Establishment of the transformants expressing human cytochrome P450 subtypes in HepG2, and their applications on drug metabolism and toxicology. Toxicol In Vitro 2001;15:245-56
86. Hashizume T, Yoshitomi S, Asahi S, et al. Advantages of human hepatocyte-derived transformants expressing a series of human cytochrome p450 isoforms for genotoxicity examination. Toxicol Sci 2010;116:488-97
87. Dai Y, Cederbaum AI. Cytotoxicity of acetaminophen in human cytochrome P4502E1-transfected HepG2 cells. J Pharmacol Exp Ther 1995;273:1497-505
88. Holownia A, Braszko JJ. Tamoxifen cytotoxicity in hepatoblastoma cells stably transfected with human CYP3A4. Biochem Pharmacol 2004;67:1057-64
89. Vignati L, Turlizzi E, Monaci S, et al. An in vitro approach to detect metabolite toxicity due to CYP3A4-dependent bioactivation of xenobiotics. Toxicology 2005;216:154-67
90. Tolosa L, Donato MT, Perez-Cataldo G, et al. Upgrading cytochrome P450 activity in HepG2 cells co-transfected with adenoviral vectors for drug hepatotoxicity assessment. Toxicol In Vitro 2012;26:1272-7
91. Tolosa L, Gomez-Lechon MJ, Perez-Cataldo G, et al. HepG2 cells simultaneously expressing five P450 enzymes for the screening of hepatotoxicity: identification of bioactivable drugs and the potential mechanism of toxicity involved. Arch Toxicol 2013;87:1115-27
92. Kia R, Sison RL, Heslop J, et al. Stem cell-derived hepatocytes as a predictive model for drug-induced liver injury: are we there yet? Br J Clin Pharmacol 2013;75:885-96
93. Baxter MA, Rowe C, Alder J, et al. Generating hepatic cell lineages from pluripotent stem cells for drug toxicity screening. Stem Cell Res 2010;5:4-22
94. Duan Y, Ma X, Zou W, et al. Differentiation and characterization of metabolically functioning hepatocytes from human embryonic stem cells. Stem Cells 2010;28:674-86
95. Pal R, Mamidi MK, Das AK, et al. A simple and economical route to generate functional hepatocyte-like cells from hESCs and their application in evaluating alcohol induced liver damage. J Cell Biochem 2012;113:19-30
96. Kang SJ, Jeong SH, Kim EJ, et al. Evaluation of hepatotoxicity of chemicals using hepatic progenitor and hepatocyte-like cells derived from mouse embryonic stem cells: effect of chemicals on ESC-derived hepatocyte differentiation. Cell Biol Toxicol 2013;29:1-11
97. Takayama K, Kawabata K, Nagamoto Y, et al. 3D spheroid culture of hESC/hiPSC-derived hepatocyte-like cells for drug toxicity testing. Biomaterials 2013;34:1781-9
98. Katsuda T, Sakai Y, Ochiya T. Induced pluripotent stem cell-derived hepatocytes as an alternative to human adult hepatocytes. J Stem Cells 2012;7:1-17
99. Yi F, Liu GH, Izpisua Belmonte JC. Human induced pluripotent stem cells derived hepatocytes: rising promise for disease modeling, drug development and cell therapy. Protein Cell 2012;3:246-50
100. Guguen-Guillouzo C, Corlu A, Guillouzo A. Stem cell-derived hepatocytes and their use in toxicology. Toxicology 2010;270:3-9
101. Liu H, Ye Z, Kim Y, et al. Generation of endoderm-derived human induced pluripotent stem cells from primary hepatocytes. Hepatology 2010;51:1810-19
102. Medine CN, Lucendo-Villarin B, Storck C, et al. Developing high-fidelity hepatotoxicity models from pluripotent stem cells. Stem Cells Transl Med 2013;2:505-9.
103. Si-Tayeb K, Noto FK, Nagaoka M, et al. Highly efficient generation of human hepatocyte-like cells from induced pluripotent stem cells. Hepatology 2010;51:297-305
104. Gieseck RL, Hannan NR, Bort R, et al. Maturation of induced pluripotent stem cell derived hepatocytes by 3D-culture. PLoS One 2014;9:e86372
105. Anson BD, Kolaja KL, Kamp TJ. Opportunities for use of human iPS cells in predictive toxicology. Clin Pharmacol Ther 2011;89:754-8
106. Sahi J, Hamilton G, Sinz M, et al. Effect of troglitazone on cytochrome P450 enzymes in primary cultures of human and rat hepatocytes. Xenobiotica 2000;30:273-84
107. Tuschl G, Lauer B, Mueller SO. Primary hepatocytes as a model to analyze species-specific toxicity and drug metabolism. Expert Opin Drug Metab Toxicol 2008;4:855-70
108. Uehara T, Kiyosawa N, Shimizu T, et al. Species-specific differences in coumarininduced hepatotoxicity as an example toxicogenomics-based approach to assessing risk of toxicity to humans. Hum Exp Toxicol 2008;27:23-35
109. Lauer B, Tuschl G, Kling M, et al. Species-specific toxicity of diclofenac and troglitazone in primary human and rat hepatocytes. Chem Biol Interact 2009;179:17-24
110. Mathijs K, Kienhuis AS, Brauers KJ, et al. Assessing the metabolic competence of sandwich-cultured mouse primary hepatocytes. Drug Metab Dispos 2009;37:1305-11
111. Guguen-Guillouzo C, Guillouzo A. General review on in vitro hepatocyte models and their applications. Methods Mol Biol 2010;640:1-40
112. Ohno M, Motojima K, Okano T, et al. Up-regulation of drug-metabolizing enzyme genes in layered co-culture of a human liver cell line and endothelial cells. Tissue Eng Part A 2008;14:1861-9
113. Guzzardi MA, Vozzi F, Ahluwalia AD. Study of the crosstalk between hepatocytes and endothelial cells using a novel multicompartmental bioreactor: a comparison between connected cultures and cocultures. Tissue Eng Part A 2009;15:3635-44
114. Krause P, Saghatolislam F, Koenig S, et al. Maintaining hepatocyte differentiation in vitro through co-culture with hepatic stellate cells. In Vitro Cell Dev Biol Anim 2009;45:205-12
115. Dash A, Inman W, Hoffmaster K, et al. Liver tissue engineering in the evaluation of drug safety. Expert Opin Drug Metab Toxicol 2009;5:1159-74
116. Domansky K, Inman W, Serdy J, et al. Perfused multiwell plate for 3D liver tissue engineering. Lab Chip 2010;10:51-8
117. Miranda JP, Rodrigues A, Tostoes RM, et al. Extending hepatocyte functionality for drug-testing applications using high-viscosity alginate-encapsulated three-dimensional cultures in bioreactors. Tissue Eng Part C Methods 2010;16:1223-32
118. Schmelzer E, Triolo F, Turner ME, et al. Three-dimensional perfusion bioreactor culture supports differentiation of human fetal liver cells. Tissue Eng Part A 2010;16:2007-16
119. Mueller D, Tascher G, Muller-Vieira U. In-depth physiological characterization of primary human hepatocytes in a 3D hollow-fiber bioreactor. J Tissue Eng Regen Med 2011;5:e207-18
120. Legendre A, Baudoin R, Alberto G, et al. Metabolic characterization of primary rat hepatocytes cultivated in parallel microfluidic biochips. J Pharm Sci 2013;102:3264-76
121. Hegde M, Jindal R, Bhushan A, et al. Dynamic interplay of flow and collagen stabilizes primary hepatocytes culture in a microfluidic platform. Lab Chip 2014;14:2033-9
122. Li CY, Stevens KR, Schwartz RE, et al. Micropatterned cell-cell interactions enable functional encapsulation of primary hepatocytes in hydrogel microtissues. Tissue Eng Part A 2014;20(15-16):2200-12
123. Cheng N, Wauthier E, Reid LM. Mature human hepatocytes from ex vivo differentiation of alginate-encapsulated hepatoblasts. Tissue Eng Part A 2008;14:1-7
124. Kobayashi A, Yamakoshi K, Yajima Y, et al. Preparation of stripe-patterned heterogeneous hydrogel sheets using microfluidic devices for high-density coculture of hepatocytes and fibroblasts. J Biosci Bioeng 2013;116:761-7
125. Leite SB, Wilk-Zasadna I, Zaldivar JM, et al. Three-dimensional HepaRG model as an attractive tool for toxicity testing. Toxicol Sci 2012;130:106-16
126. Narjoz C, Marisa L, Imbeaud S, et al. Genomic consequences of cytochrome P450 2C9 overexpression in human hepatoma cells. Chem Res Toxicol 2009;22:779-87
127. Loya K, Eggenschwiler R, Ko K, et al. Hepatic differentiation of pluripotent stem cells. Biol Chem 2009;390:1047-55