Generation of Hepatocyte-Like Cells from Human Pluripotent Stem Cells

Chapter

Abstract

The parenchymal cell of the liver is the hepatocyte. It is responsible for many of the functions associated with the liver including the secretion of serum proteins, regulation of carbohydrate metabolism, control of cholesterol and lipid flux, and oxidation of xenobiotics and pharmaceuticals. Significant advances have been made toward controlling the differentiation of human pluripotent stem cells with several publications describing the generation of cells that exhibit hepatocyte characteristics. These induced hepatocyte-like cells are useful for studying the molecular basis of cell differentiation and mechanisms of liver disease. In addition, because pluripotent stem cells can self-renew indefinitely, such cells could potentially provide a limitless supply of exogenous human hepatocytes for drug toxicity studies and for cell transplant therapy. Despite tremendous progress, the differentiation of pluripotent cells toward a hepatic fate yields cells that are similar yet not identical to primary hepatocytes. Here we discuss recent progress as well as the limitations associated with hepatocytes produced from human pluripotent stem cells.

Keywords

Cholesterol Zinc Migration Hepatitis Albumin 

Abbreviations

AFP

Alpha-fetoprotein

BMP

Bone morphogenetic protein

CYP450

Cytochrome P450

ESCs

Embryonic stem cells

FGF

Fibroblast growth factor

HGF

Hepatocyte growth factor

HNF4a

Hepatocyte nuclear factor 4 alpha

iPSCs

Induced pluripotent stem cells

LDL

Low density lipoprotein

OSM

Oncostatin M

TGFb

Transforming growth factor beta

TTR

Transthyretin

References

  1. 1.
    Sherlock S, Dooley J. Diseases of the liver and biliary system. Oxford, UK: Blackwell Science; 1997.Google Scholar
  2. 2.
    Grompe M. Principles of therapeutic liver repopulation. J Inherit Metab Dis. 2006;29:421–5.PubMedGoogle Scholar
  3. 3.
    Fox IJ, Chowdhury JR, Kaufman SS, et al. Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantation. N Engl J Med. 1998;338:1422–6.PubMedGoogle Scholar
  4. 4.
    Lerou PH, Daley GQ. Therapeutic potential of embryonic stem cells. Blood Rev. 2005;19:321–31.PubMedGoogle Scholar
  5. 5.
    Martin GR. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci U S A. 1981;78:7634–8.PubMedGoogle Scholar
  6. 6.
    Lavon N, Yanuka O, Benvenisty N. Differentiation and isolation of hepatic-like cells from human embryonic stem cells. Differentiation. 2004;72:230–8.PubMedGoogle Scholar
  7. 7.
    Baharvand H, Hashemi SM, Kazemi Ashtiani S, Farrokhi A. Differentiation of human embryonic stem cells into hepatocytes in 2D and 3D culture systems in vitro. Int J Dev Biol. 2006;50: 645–52.PubMedGoogle Scholar
  8. 8.
    Basma H, Soto-Gutierrez A, Yannam GR, et al. Differentiation and transplantation of human embryonic stem cell-derived hepatocytes. Gastroenterology. 2009;136:990–9.PubMedGoogle Scholar
  9. 9.
    Duan Y, Catana A, Meng Y, et al. Differentiation and enrichment of hepatocyte-like cells from human embryonic stem cells in vitro and in vivo. Stem Cells. 2007;25:3058–68.PubMedGoogle Scholar
  10. 10.
    Fletcher J, Cui W, Samuel K, et al. The inhibitory role of stromal cell mesenchyme on human embryonic stem cell hepatocyte differentiation is overcome by Wnt3a treatment. Cloning Stem Cells. 2008;10:331–9.PubMedGoogle Scholar
  11. 11.
    Ghodsizadeh A, Taei A, Totonchi M, et al. Generation of liver disease-specific induced pluripotent stem cells along with efficient differentiation to functional hepatocyte-like cells. Stem Cell Rev. 2010;6:622–32.PubMedGoogle Scholar
  12. 12.
    Lu H, Wang Z, Zheng Q, Li JH, Chong XQ, Xiao SD. Efficient differentiation of newly derived human embryonic stem cells from discarded blastocysts into hepatocyte-like cells. J Dig Dis. 2010;11:376–82.PubMedGoogle Scholar
  13. 13.
    Pei H, Yang Y, Xi J, et al. Lineage restriction and differentiation of human embryonic stem cells into hepatic progenitors and zone 1 hepatocytes. Tissue Eng Part C Methods. 2009;15:95–104.PubMedGoogle Scholar
  14. 14.
    Rambhatla L, Chiu CP, Kundu P, Peng Y, Carpenter MK. Generation of hepatocyte-like cells from human embryonic stem cells. Cell Transplant. 2003;12:1–11.PubMedGoogle Scholar
  15. 15.
    Schwartz RE, Linehan JL, Painschab MS, Hu WS, Verfaillie CM, Kaufman DS. Defined conditions for development of functional hepatic cells from human embryonic stem cells. Stem Cells Dev. 2005;14:643–55.PubMedGoogle Scholar
  16. 16.
    Shirahashi H, Wu J, Yamamoto N, et al. Differentiation of human and mouse embryonic stem cells along a hepatocyte lineage. Cell Transplant. 2004;13:197–211.PubMedGoogle Scholar
  17. 17.
    Soto-Gutierrez A, Navarro-Alvarez N, Rivas-Carrillo JD, et al. Differentiation of human embryonic stem cells to hepatocytes using deleted variant of HGF and poly-amino-urethane-coated nonwoven polytetrafluoroethylene fabric. Cell Transplant. 2006;15:335–41.PubMedGoogle Scholar
  18. 18.
    Woo DH, Kim SK, Lim HJ, et al. Direct and indirect contribution of human embryonic stem cell-derived hepatocyte-like cells to liver repair in mice. Gastroenterology. 2012;142:602–11.PubMedGoogle Scholar
  19. 19.
    Yu YD, Kim KH, Lee SG, et al. Hepatic differentiation from human embryonic stem cells using stromal cells. J Surg Res. 2011;170:e253–61.PubMedGoogle Scholar
  20. 20.
    Chiao E, Elazar M, Xing Y, et al. Isolation and transcriptional profiling of purified hepatic cells derived from human embryonic stem cells. Stem Cells. 2008;26:2032–41.PubMedGoogle Scholar
  21. 21.
    Ishii T, Yasuchika K, Fukumitsu K, et al. In vitro hepatic maturation of human embryonic stem cells by using a mesenchymal cell line derived from murine fetal livers. Cell Tissue Res. 2010;339:505–12.PubMedGoogle Scholar
  22. 22.
    Si-Tayeb K, Lemaigre FP, Duncan SA. Organogenesis and development of the liver. Dev Cell. 2010;18:175–89.PubMedGoogle Scholar
  23. 23.
    Zaret KS. Genetic programming of liver and pancreas progenitors: lessons for stem-cell differentiation. Nat Rev Genet. 2008;9: 329–40.PubMedGoogle Scholar
  24. 24.
    Zorn AM, Wells JM. Vertebrate endoderm development and organ formation. Annu Rev Cell Dev Biol. 2009;25:221–51.PubMedGoogle Scholar
  25. 25.
    Zorn AM. Liver Development. Stembook [Internet] Cambridge (MA) Harvard Stem Cell Institute; 2008.Google Scholar
  26. 26.
    Kamiya A, Kinoshita T, Ito Y, et al. Fetal liver development requires a paracrine action of oncostatin M through the gp130 signal transducer. EMBO J. 1999;18:2127–36.PubMedGoogle Scholar
  27. 27.
    D’Amour KA, Agulnick AD, Eliazer S, Kelly OG, Kroon E, Baetge EE. Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat Biotechnol. 2005;23:1534–41.PubMedGoogle Scholar
  28. 28.
    McLean AB, D’Amour KA, Jones KL, et al. Activin a efficiently specifies definitive endoderm from human embryonic stem cells only when phosphatidylinositol 3-kinase signaling is suppressed. Stem Cells. 2007;25:29–38.PubMedGoogle Scholar
  29. 29.
    Delaforest A, Nagaoka M, Si-Tayeb K, et al. HNF4A is essential for specification of hepatic progenitors from human pluripotent stem cells. Development. 2011;138:4143–53.PubMedGoogle Scholar
  30. 30.
    Thomas PQ, Brown A, Beddington RS. Hex: a homeobox gene revealing peri-implantation asymmetry in the mouse embryo and an early transient marker of endothelial cell precursors. Development. 1998;125:85–94.PubMedGoogle Scholar
  31. 31.
    Watt AJ, Zhao R, Li J, Duncan SA. Development of the mammalian liver and ventral pancreas is dependent on GATA4. BMC Dev Biol. 2007;7:37.PubMedGoogle Scholar
  32. 32.
    Bouwmeester T, Kim S, Sasai Y, Lu B, De Robertis EM. Cerberus is a head-inducing secreted factor expressed in the anterior endoderm of Spemann’s organizer. Nature. 1996;382:595–601.PubMedGoogle Scholar
  33. 33.
    D’Amour KA, Bang AG, Eliazer S, et al. Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat Biotechnol. 2006;24:1392–401.PubMedGoogle Scholar
  34. 34.
    Hay DC, Fletcher J, Payne C, et al. Highly efficient differentiation of hESCs to functional hepatic endoderm requires ActivinA and Wnt3a signaling. Proc Natl Acad Sci U S A. 2008;105:12301–6.PubMedGoogle Scholar
  35. 35.
    Brown S, Teo A, Pauklin S, et al. Activin/nodal signaling controls divergent transcriptional networks in human embryonic stem cells and in endoderm progenitors. Stem Cells. 2011;29:1176–85.PubMedGoogle Scholar
  36. 36.
    Chen YF, Tseng CY, Wang HW, Kuo HC, Yang VW, Lee OK. Rapid generation of mature hepatocyte-like cells from human induced pluripotent stem cells by an efficient three-step protocol. Hepatology. 2012;55:1193–203.PubMedGoogle Scholar
  37. 37.
    Spence JR, Mayhew CN, Rankin SA, et al. Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature. 2011;470:105–9.PubMedGoogle Scholar
  38. 38.
    Green MD, Chen A, Nostro MC, et al. Generation of anterior foregut endoderm from human embryonic and induced pluripotent stem cells. Nat Biotechnol. 2011;29:267–72.PubMedGoogle Scholar
  39. 39.
    Jung J, Zheng M, Goldfarb M, Zaret KS. Initiation of mammalian liver development from endoderm by fibroblast growth factors. Science. 1999;284:1998–2003.PubMedGoogle Scholar
  40. 40.
    Rossi JM, Dunn NR, Hogan BL, Zaret KS. Distinct mesodermal signals, including BMPs from the septum transversum mesenchyme, are required in combination for hepatogenesis from the endoderm. Genes Dev. 2001;15:1998–2009.PubMedGoogle Scholar
  41. 41.
    Keng VW, Yagi H, Ikawa M, et al. Homeobox gene Hex is essential for onset of mouse embryonic liver development and differentiation of the monocyte lineage. Biochem Biophys Res Commun. 2000;276:1155–61.PubMedGoogle Scholar
  42. 42.
    Martinez Barbera JP, Clements M, Thomas P, et al. The homeobox gene Hex is required in definitive endodermal tissues for normal forebrain, liver and thyroid formation. Development. 2000;127: 2433–45.PubMedGoogle Scholar
  43. 43.
    Li J, Ning G, Duncan SA. Mammalian hepatocyte differentiation requires the transcription factor HNF-4alpha. Genes Dev. 2000;14: 464–74.PubMedGoogle Scholar
  44. 44.
    Suzuki A, Sekiya S, Buscher D, Izpisua Belmonte JC, Taniguchi H. Tbx3 controls the fate of hepatic progenitor cells in liver development by suppressing p19ARF expression. Development. 2008; 135:1589–95.PubMedGoogle Scholar
  45. 45.
    Ludtke TH, Christoffels VM, Petry M, Kispert A. Tbx3 promotes liver bud expansion during mouse development by suppression of cholangiocyte differentiation. Hepatology. 2009;49:969–78.PubMedGoogle Scholar
  46. 46.
    Lokmane L, Haumaitre C, Garcia-Villalba P, Anselme I, Schneider-Maunoury S, Cereghini S. Crucial role of vHNF1 in vertebrate hepatic specification. Development. 2008;135:2777–86.PubMedGoogle Scholar
  47. 47.
    Brolen G, Sivertsson L, Bjorquist P, et al. Hepatocyte-like cells derived from human embryonic stem cells specifically via definitive endoderm and a progenitor stage. J Biotechnol. 2010;145:284–94.PubMedGoogle Scholar
  48. 48.
    Chen Y, Soto-Gutierrez A, Navarro-Alvarez N, et al. Instant hepatic differentiation of human embryonic stem cells using activin A and a deleted variant of HGF. Cell Transplant. 2006;15:865–71.PubMedGoogle Scholar
  49. 49.
    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.PubMedGoogle Scholar
  50. 50.
    Ishii T, Fukumitsu K, Yasuchika K, et al. Effects of extracellular matrixes and growth factors on the hepatic differentiation of human embryonic stem cells. Am J Physiol Gastrointest Liver Physiol. 2008;295:G313–21.PubMedGoogle Scholar
  51. 51.
    Roelandt P, Pauwelyn KA, Sancho-Bru P, et al. Human embryonic and rat adult stem cells with primitive endoderm-like phenotype can be fated to definitive endoderm, and finally hepatocyte-like cells. PLoS One. 2010;5:e12101.PubMedGoogle Scholar
  52. 52.
    Shiraki N, Yamazoe T, Qin Z, et al. Efficient differentiation of embryonic stem cells into hepatic cells in vitro using a feeder-free basement membrane substratum. PLoS One. 2011;6:e24228.PubMedGoogle Scholar
  53. 53.
    Touboul T, Hannan NR, Corbineau S, et al. Generation of functional hepatocytes from human embryonic stem cells under chemically defined conditions that recapitulate liver development. Hepatology. 2010;51:1754–65.PubMedGoogle Scholar
  54. 54.
    Asgari S, Moslem M, Bagheri-Lankarani K, Pournasr B, Miryounesi M, Baharvand H. Differentiation and transplantation of human induced pluripotent stem cell-derived hepatocyte-like cells. Stem Cell Rev. 2011.Google Scholar
  55. 55.
    Cai J, Zhao Y, Liu Y, et al. Directed differentiation of human embryonic stem cells into functional hepatic cells. Hepatology. 2007;45:1229–39.PubMedGoogle Scholar
  56. 56.
    Farzaneh Z, Pournasr B, Ebrahimi M, Aghdami N, Baharvand H. Enhanced functions of human embryonic stem cell-derived hepatocyte-like cells on three-dimensional nanofibrillar surfaces. Stem Cell Rev. 2010;6:601–10.PubMedGoogle Scholar
  57. 57.
    Funakoshi N, Duret C, Pascussi JM, et al. Comparison of hepatic-like cell production from human embryonic stem cells and adult liver progenitor cells: CAR transduction activates a battery of detoxification genes. Stem Cell Rev. 2011;7(3):518–31.PubMedGoogle Scholar
  58. 58.
    Hay DC, Zhao D, Fletcher J, et al. Efficient differentiation of hepatocytes from human embryonic stem cells exhibiting markers recapitulating liver development in vivo. Stem Cells. 2008;26: 894–902.PubMedGoogle Scholar
  59. 59.
    Inamura M, Kawabata K, Takayama K, et al. Efficient generation of hepatoblasts from human ES cells and iPS cells by transient overexpression of homeobox gene HEX. Mol Ther. 2011;19:400–7.PubMedGoogle Scholar
  60. 60.
    Kim N, Kim H, Jung I, Kim Y, Kim D, Han YM. Expression profiles of miRNAs in human embryonic stem cells during hepatocyte differentiation. Hepatol Res. 2011;41:170–83.PubMedGoogle Scholar
  61. 61.
    Medine CN, Lucendo-Villarin B, Zhou W, West CC, Hay DC. Robust generation of hepatocyte-like cells from human embryonic stem cell populations. J Vis Exp. 2011;56:e2969.PubMedGoogle Scholar
  62. 62.
    Rashid ST, Corbineau S, Hannan N, et al. Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells. J Clin Invest. 2010;120:3127–36.PubMedGoogle Scholar
  63. 63.
    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.PubMedGoogle Scholar
  64. 64.
    Song Z, Cai J, Liu Y, et al. Efficient generation of hepatocyte-like cells from human induced pluripotent stem cells. Cell Res. 2009;19:1233–42.PubMedGoogle Scholar
  65. 65.
    Sullivan GJ, Hay DC, Park IH, et al. Generation of functional human hepatic endoderm from human induced pluripotent stem cells. Hepatology. 2010;51:329–35.PubMedGoogle Scholar
  66. 66.
    Takata A, Otsuka M, Kogiso T, et al. Direct differentiation of hepatic cells from human induced pluripotent stem cells using a limited number of cytokines. Hepatol Int. 2011;5:890–898.Google Scholar
  67. 67.
    Takayama K, Inamura M, Kawabata K, et al. Efficient and directive generation of two distinct endoderm lineages from human ESCs and iPSCs by differentiation stage-specific SOX17 transduction. PLoS One. 2011;6:e21780.PubMedGoogle Scholar
  68. 68.
    Takayama K, Inamura M, Kawabata K, et al. Efficient generation of functional hepatocytes from human embryonic stem cells and induced pluripotent stem cells by HNF4alpha transduction. Mol Ther. 2012;20:127–37.PubMedGoogle Scholar
  69. 69.
    Kamiya A, Kinoshita T, Miyajima A. Oncostatin M and hepatocyte growth factor induce hepatic maturation via distinct signaling pathways. FEBS Lett. 2001;492:90–4.PubMedGoogle Scholar
  70. 70.
    Kinoshita T, Sekiguchi T, Xu MJ, et al. Hepatic differentiation induced by oncostatin M attenuates fetal liver hematopoiesis. Proc Natl Acad Sci U S A. 1999;96:7265–70.PubMedGoogle Scholar
  71. 71.
    Agarwal S, Holton KL, Lanza R. Efficient differentiation of functional hepatocytes from human embryonic stem cells. Stem Cells. 2008;26:1117–27.PubMedGoogle Scholar
  72. 72.
    Liu H, Kim Y, Sharkis S, Marchionni L, Jang YY. In vivo liver regeneration potential of human induced pluripotent stem cells from diverse origins. Sci Transl Med. 2011;3(82):82ra39.PubMedGoogle Scholar
  73. 73.
    Jozefczuk J, Prigione A, Chavez L, Adjaye J. Comparative analysis of human embryonic stem cell and induced pluripotent stem cell-derived hepatocyte-like cells reveals current drawbacks and possible strategies for improved differentiation. Stem Cells Dev. 2011;20:1259–75.PubMedGoogle Scholar
  74. 74.
    Zamule SM, Coslo DM, Chen F, Omiecinski CJ. Differentiation of human embryonic stem cells along a hepatic lineage. Chem Biol Interact. 2011;190:62–72.PubMedGoogle Scholar
  75. 75.
    Berthiaume F, Moghe PV, Toner M, Yarmush ML. Effect of extracellular matrix topology on cell structure, function, and physiological responsiveness: hepatocytes cultured in a sandwich configuration. FASEB J. 1996;10:1471–84.PubMedGoogle Scholar
  76. 76.
    Dunn JC, Tompkins RG, Yarmush ML. Long-term in vitro function of adult hepatocytes in a collagen sandwich configuration. Biotechnol Prog. 1991;7:237–45.PubMedGoogle Scholar
  77. 77.
    Fawcett DW, Raviola E. Bloom and Fawcett, a textbook of histology. New York, NY: Chapman & Hall; 1994.Google Scholar
  78. 78.
    Nagamoto Y, Tashiro K, Takayama K, et al. The promotion of hepatic maturation of human pluripotent stem cells in 3D co-culture using type I collagen and Swiss 3T3 cell sheets. Biomaterials. 2012;33:4526–34.PubMedGoogle Scholar
  79. 79.
    Miki T, Ring A, Gerlach J. Hepatic differentiation of human embryonic stem cells is promoted by three-dimensional dynamic perfusion culture conditions. Tissue Eng Part C Methods. 2011;17:557–68.PubMedGoogle Scholar
  80. 80.
    Khetani SR, Chen AA, Ranscht B, Bhatia SN. T-cadherin modulates hepatocyte functions in vitro. FASEB J. 2008;22:3768–75.PubMedGoogle Scholar
  81. 81.
    Khetani SR, Bhatia SN. Microscale culture of human liver cells for drug development. Nat Biotechnol. 2008;26:120–6.PubMedGoogle Scholar
  82. 82.
    Kim Y, Rajagopalan P. 3D hepatic cultures simultaneously maintain primary hepatocyte and liver sinusoidal endothelial cell phenotypes. PLoS One. 2010;5:e15456.PubMedGoogle Scholar
  83. 83.
    Soto-Gutierrez A, Navarro-Alvarez N, Yagi H, Nahmias Y, Yarmush ML, Kobayashi N. Engineering of an hepatic organoid to develop liver assist devices. Cell Transplant. 2010;19:815–22.PubMedGoogle Scholar
  84. 84.
    Azuma H, Paulk N, Ranade A, et al. Robust expansion of human hepatocytes in Fah−/−/Rag2−/−/Il2rg−/− mice. Nat Biotechnol. 2007;25:903–10.PubMedGoogle Scholar
  85. 85.
    Bissig KD, Le TT, Woods NB, Verma IM. Repopulation of adult and neonatal mice with human hepatocytes: a chimeric animal model. Proc Natl Acad Sci U S A. 2007;104:20507–11.PubMedGoogle Scholar
  86. 86.
    Bissig KD, Wieland SF, Tran P, et al. Human liver chimeric mice provide a model for hepatitis B and C virus infection and treatment. J Clin Invest. 2010;120:924–30.PubMedGoogle Scholar
  87. 87.
    Meuleman P, Libbrecht L, De Vos R, et al. Morphological and biochemical characterization of a human liver in a uPA-SCID mouse chimera. Hepatology. 2005;41:847–56.PubMedGoogle Scholar
  88. 88.
    Tateno C, Yoshizane Y, Saito N, et al. Near completely humanized liver in mice shows human-type metabolic responses to drugs. Am J Pathol. 2004;165:901–12.PubMedGoogle Scholar
  89. 89.
    Choi SM, Kim Y, Liu H, Chaudhari P, Ye Z, Jang YY. Liver engraftment potential of hepatic cells derived from patient-specific induced pluripotent stem cells. Cell Cycle. 2011;10: 2423–7.PubMedGoogle Scholar
  90. 90.
    Payne CM, Samuel K, Pryde A, et al. Persistence of functional hepatocyte-like cells in immune-compromised mice. Liver Int. 2011;31:254–62.PubMedGoogle Scholar
  91. 91.
    Espejel S, Roll GR, McLaughlin KJ, et al. Induced pluripotent stem cell-derived hepatocytes have the functional and proliferative capabilities needed for liver regeneration in mice. J Clin Invest. 2010;120:3120–6.PubMedGoogle Scholar
  92. 92.
    Wu G, Liu N, Rittelmeyer I, et al. Generation of healthy mice from gene-corrected disease-specific induced pluripotent stem cells. PLoS Biol. 2011;9:e1001099.PubMedGoogle Scholar
  93. 93.
    Yamanouchi K, Zhou H, Roy-Chowdhury N, et al. Hepatic irradiation augments engraftment of donor cells following hepatocyte transplantation. Hepatology. 2009;49:258–67.PubMedGoogle Scholar
  94. 94.
    Yildirimman R, Brolen G, Vilardell M, et al. Human embryonic stem cell derived hepatocyte-like cells as a tool for in vitro hazard assessment of chemical carcinogenicity. Toxicol Sci. 2011;124: 278–90.PubMedGoogle Scholar
  95. 95.
    Cayo MA, Cai J, Delaforest A, et al. ‘JD’ iPS cell-derived hepatocytes faithfully recapitulate the pathophysiology of familial hypercholesterolemia. Hepatology. 2012;56(6):2163–71.PubMedGoogle Scholar
  96. 96.
    Park IH, Arora N, Huo H, et al. Disease-specific induced pluripotent stem cells. Cell. 2008;134:877–86.PubMedGoogle Scholar
  97. 97.
    Yusa K, Rashid ST, Strick-Marchand H, et al. Targeted gene correction of alpha1-antitrypsin deficiency in induced pluripotent stem cells. Nature. 2011;478:391–4.PubMedGoogle Scholar
  98. 98.
    Goldstein JL, Brown MS. The LDL receptor. Arterioscler Thromb Vasc Biol. 2009;29:431–8.PubMedGoogle Scholar
  99. 99.
    Sniderman AD, De Graaf J, Couture P, Williams K, Kiss RS, Watts GF. Regulation of plasma LDL: the apoB paradigm. Clin Sci (Lond). 2010;118:333–9.Google Scholar
  100. 100.
    Davis CG, Lehrman MA, Russell DW, Anderson RG, Brown MS, Goldstein JL. The J.D. mutation in familial hypercholesterolemia: amino acid substitution in cytoplasmic domain impedes internalization of LDL receptors. Cell. 1986;45:15–24.PubMedGoogle Scholar
  101. 101.
    Schwartz RE, Trehan K, Andrus L, et al. Modeling hepatitis C virus infection using human induced pluripotent stem cells. Proc Natl Acad Sci U S A. 2012;109:2544–8.PubMedGoogle Scholar
  102. 102.
    Wu X, Robotham JM, Lee E, et al. Productive hepatitis C virus infection of stem cell-derived hepatocytes reveals a critical transition to viral permissiveness during differentiation. PLoS Pathog. 2012;8:e1002617.PubMedGoogle Scholar
  103. 103.
    Fisher RA, Strom SC. Human hepatocyte transplantation: worldwide results. Transplantation. 2006;82:441–9.PubMedGoogle Scholar
  104. 104.
    Hickey RD, Lillegard JB, Fisher JE, et al. Efficient production of Fah-null heterozygote pigs by chimeric adeno-associated virus-mediated gene knockout and somatic cell nuclear transfer. Hepatology. 2011;54(4):1351–9.PubMedGoogle Scholar
  105. 105.
    Chen AA, Thomas DK, Ong LL, Schwartz RE, Golub TR, Bhatia SN. Humanized mice with ectopic artificial liver tissues. Proc Natl Acad Sci U S A. 2011;108:11842–7.PubMedGoogle Scholar
  106. 106.
    Kelly OG, Chan MY, Martinson LA, et al. Cell-surface markers for the isolation of pancreatic cell types derived from human embryonic stem cells. Nat Biotechnol. 2011;29:750–6.PubMedGoogle Scholar
  107. 107.
    Kroon E, Martinson LA, Kadoya K, et al. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol. 2008;26:443–52.PubMedGoogle Scholar

Copyright information

© Springer Science + Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Cell Biology, Neurobiology, and AnatomyMedical College of WisconsinMilwaukeeUSA

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