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Hepatocytes

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Molecular Pathology of Liver Diseases

Part of the book series: Molecular Pathology Library ((MPLB,volume 5))

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Abstract

The ability of the liver to regenerate was recognized by the Greeks in the ancient myth of Prometheus, the Titan god of forethought, who gave fire to the mortals and angered Zeus. Zeus then punished him for his crime by having him bound to a rock while a great eagle ate his liver every day only to have it grow back to be eaten again the next day [1]. In contrast to other solid organs, the human liver has the unique ability to regenerate after toxic injury, chronic inflammation, and surgical resection and is able to restore its original mass, cellular structure and functions [1–3].

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References

  1. Power C, Rasko JE. Whither Prometheus’ liver? Greek myth and the science of regeneration. Ann Intern Med. 2008;149(6):421–6.

    Article  PubMed  Google Scholar 

  2. Michalopoulos GK. Liver regeneration. J Cell Physiol. 2007;213(2):286–300.

    Article  PubMed  CAS  Google Scholar 

  3. Duncan AW, Dorrell C, Grompe M. Stem cells and liver regeneration. Gastroenterology. 2009;137(2):466–81.

    Article  PubMed  Google Scholar 

  4. Grompe M. The origin of hepatocytes. Gastroenterology. 2005;128(7):2158–60.

    Article  PubMed  Google Scholar 

  5. Brauer RW. Liver circulation and function. Physiol Rev. 1963;43:115–213.

    PubMed  CAS  Google Scholar 

  6. Brauer RW. Hepatic blood flow and its relation to hepatic function. Am J Dig Dis. 1963;8:564–76.

    Article  PubMed  CAS  Google Scholar 

  7. Arias IM, Che M, Gatmaitan Z, Leveille C, Nishida T, St Pierre M. The biology of the bile canaliculus, 1993. Hepatology. 1993;17(2):318–29.

    Article  PubMed  CAS  Google Scholar 

  8. Stamatoglou SC, Hughes RC. Cell adhesion molecules in liver function and pattern formation. FASEB J. 1994;8(6):420–7.

    PubMed  CAS  Google Scholar 

  9. Baratta JL, Ngo A, Lopez B, Kasabwalla N, Longmuir KJ, Robertson RT. Cellular organization of normal mouse liver: a histological, quantitative immunocytochemical, and fine structural analysis. Histochem Cell Biol. 2009;131(6):713–26.

    Article  PubMed  CAS  Google Scholar 

  10. Berry MN, Friend DS. High-yield preparation of isolated rat liver parenchymal cells: a biochemical and fine structural study. J Cell Biol. 1969;43(3):506–20.

    Article  PubMed  CAS  Google Scholar 

  11. Strom SC, Jirtle RL, Jones RS, et al. Isolation, culture, and transplantation of human hepatocytes. J Natl Cancer Inst. 1982;68(5):771–8.

    PubMed  CAS  Google Scholar 

  12. Holzman MD, Rozga J, Neuzil DF, Griffin D, Moscioni AD, Demetriou AA. Selective intraportal hepatocyte transplantation in analbuminemic and Gunn rats. Transplantation. 1993;55(6):1213–9.

    Article  PubMed  CAS  Google Scholar 

  13. Navarro-Alvarez N, Soto-Gutierrez A, Rivas-Carrillo JD, et al. Self-assembling peptide nanofiber as a novel culture system for isolated porcine hepatocytes. Cell Transplant. 2006;15(10):921–7.

    Article  PubMed  Google Scholar 

  14. Navarro-Alvarez N, Soto-Gutierrez A, Kobayashi N. Stem cell research and therapy for liver disease. Curr Stem Cell Res Ther. 2009;4(2):141–6.

    Article  PubMed  CAS  Google Scholar 

  15. 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(7):837–54.

    Article  PubMed  CAS  Google Scholar 

  16. Hewitt NJ, 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(1):159–234.

    Article  PubMed  CAS  Google Scholar 

  17. Tanaka K, Soto-Gutierrez A, Navarro-Alvarez N, Rivas-Carrillo JD, Jun HS, Kobayashi N. Functional hepatocyte culture and its application to cell therapies. Cell Transplant. 2006;15(10):855–64.

    Article  PubMed  Google Scholar 

  18. Michalopoulos GK, Bowen WC, Mule K, Stolz DB. Histological organization in hepatocyte organoid cultures. Am J Pathol. 2001;159(5):1877–87.

    Article  PubMed  CAS  Google Scholar 

  19. Pediaditakis P, Lopez-Talavera JC, Petersen B, Monga SP, Michalopoulos GK. The processing and utilization of hepatocyte growth factor/scatter factor following partial hepatectomy in the rat. Hepatology. 2001;34(4 Pt 1):688–93.

    Article  PubMed  CAS  Google Scholar 

  20. Cho CH, Berthiaume F, Tilles AW, Yarmush ML. A new technique for primary hepatocyte expansion in vitro. Biotechnol Bioeng. 2008;101(2):345–56.

    Article  PubMed  CAS  Google Scholar 

  21. Dunn JC, Tompkins RG, Yarmush ML. Hepatocytes in collagen sandwich: evidence for transcriptional and translational regulation. J Cell Biol. 1992;116(4):1043–53.

    Article  PubMed  CAS  Google Scholar 

  22. Turncliff RZ, Meier PJ, Brouwer KL. Effect of dexamethasone treatment on the expression and function of transport proteins in sandwich-cultured rat hepatocytes. Drug Metab Dispos. 2004;32(8):834–9.

    Article  PubMed  CAS  Google Scholar 

  23. Kidambi S, Yarmush RS, Novik E, Chao P, Yarmush ML, Nahmias Y. Oxygen-mediated enhancement of primary hepatocyte metabolism, functional polarization, gene expression, and drug clearance. Proc Natl Acad Sci U S A. 2009;106:15714–9.

    Article  PubMed  CAS  Google Scholar 

  24. Jindal R, Nahmias Y, Tilles AW, Berthiaume F, Yarmush ML. Amino acid-mediated heterotypic interaction governs performance of a hepatic tissue model. FASEB J. 2009;23(7):2288–98.

    Article  PubMed  CAS  Google Scholar 

  25. Hamilton GA, Westmorel C, George AE. Effects of medium composition on the morphology and function of rat hepatocytes cultured as spheroids and monolayers. In Vitro Cell Dev Biol Anim. 2001;37(10):656–67.

    Article  PubMed  CAS  Google Scholar 

  26. Hamilton GA, Jolley SL, Gilbert D, Coon DJ, Barros S, LeCluyse EL. Regulation of cell morphology and cytochrome P450 expression in human hepatocytes by extracellular matrix and cell-cell interactions. Cell Tissue Res. 2001;306(1):85–99.

    Article  PubMed  CAS  Google Scholar 

  27. Nannelli A, Chirulli V, Longo V, Gervasi PG. Expression and induction by rifampicin of CAR- and PXR-regulated CYP2B and CYP3A in liver, kidney and airways of pig. Toxicology. 2008;252(1–3):105–12.

    Article  PubMed  CAS  Google Scholar 

  28. Lake BG, Price RJ, Giddings AM, Walters DG. In vitro assays for induction of drug metabolism. Methods Mol Biol. 2009;481:47–58.

    PubMed  CAS  Google Scholar 

  29. Sinz M, Wallace G, Sahi J. Current industrial practices in assessing CYP450 enzyme induction: preclinical and clinical. AAPS J. 2008;10(2):391–400.

    Article  PubMed  CAS  Google Scholar 

  30. Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J. 2005;5(1):6–13.

    Article  PubMed  CAS  Google Scholar 

  31. Zuber R, Anzenbacherova E, Anzenbacher P. Cytochromes P450 and experimental models of drug metabolism. J Cell Mol Med. 2002;6(2):189–98.

    Article  PubMed  CAS  Google Scholar 

  32. Lin JH, Lu AY. Inhibition and induction of cytochrome P450 and the clinical implications. Clin Pharmacokinet. 1998;35(5):361–90.

    Article  PubMed  CAS  Google Scholar 

  33. Wang H, Faucette SR, Gilbert D, et al. Glucocorticoid receptor enhancement of pregnane X receptor-mediated CYP2B6 regulation in primary human hepatocytes. Drug Metab Dispos. 2003;31(5):620–30.

    Article  PubMed  CAS  Google Scholar 

  34. Li YC, Wang DP, Chiang JY. Regulation of cholesterol 7 alpha-hydroxylase in the liver. Cloning, sequencing, and regulation of cholesterol 7 alpha-hydroxylase mRNA. J Biol Chem. 1990;265(20):12012–9.

    PubMed  CAS  Google Scholar 

  35. van Montfoort JE, Hagenbuch B, Groothuis GM, Koepsell H, Meier PJ, Meijer DK. Drug uptake systems in liver and kidney. Curr Drug Metab. 2003;4(3):185–211.

    Article  PubMed  Google Scholar 

  36. Mita S, Suzuki H, Akita H, et al. Inhibition of bile acid transport across Na+/taurocholate cotransporting polypeptide (SLC10A1) and bile salt export pump (ABCB 11)-coexpressing LLC-PK1 cells by cholestasis-inducing drugs. Drug Metab Dispos. 2006;34(9):1575–81.

    Article  PubMed  CAS  Google Scholar 

  37. Hollenberg PF. Characteristics and common properties of inhibitors, inducers, and activators of CYP enzymes. Drug Metab Rev. 2002;34(1–2):17–35.

    Article  PubMed  CAS  Google Scholar 

  38. Duncan SA, Navas MA, Dufort D, Rossant J, Stoffel M. Regulation of a transcription factor network required for differentiation and metabolism. Science. 1998;281(5377):692–5.

    Article  PubMed  CAS  Google Scholar 

  39. Runge D, Runge DM, Jager D, et al. Serum-free, long-term cultures of human hepatocytes: maintenance of cell morphology, transcription factors, and liver-specific functions. Biochem Biophys Res Commun. 2000;269(1):46–53.

    Article  PubMed  CAS  Google Scholar 

  40. Rigato I, Cravatari M, Avellini C, Ponte E, Croce SL, Tiribelli C. Drug-induced acute cholestatic liver damage in a patient with mutation of UGT1A1. Nat Clin Pract Gastroenterol Hepatol. 2007;4(7):403–8.

    Article  PubMed  CAS  Google Scholar 

  41. Kolarich D, Turecek PL, Weber A, et al. Biochemical, molecular characterization, and glycoproteomic analyses of alpha(1)-proteinase inhibitor products used for replacement therapy. Transfusion. 2006;46(11):1959–77.

    Article  PubMed  CAS  Google Scholar 

  42. Mulgrew AT, Taggart CC, McElvaney NG. Alpha-1-antitrypsin deficiency: current concepts. Lung. 2007;185(4):191–201.

    Article  PubMed  CAS  Google Scholar 

  43. Burton BK. Inborn errors of metabolism in infancy: a guide to diagnosis. Pediatrics. 1998;102(6):E69.

    Article  PubMed  CAS  Google Scholar 

  44. Falkowski O, An HJ, Ianus IA, et al. Regeneration of hepatocyte “buds” in cirrhosis from intrabiliary stem cells. J Hepatol. 2003;39(3):357–64.

    Article  PubMed  CAS  Google Scholar 

  45. Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214(2):199–210.

    Article  PubMed  CAS  Google Scholar 

  46. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119(6):1420–8.

    Article  PubMed  CAS  Google Scholar 

  47. Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transitions. J Clin Invest. 2009;119(6):1429–37.

    Article  PubMed  CAS  Google Scholar 

  48. Zavadil J, Bottinger EP. TGF-beta and epithelial-to-mesenchymal transitions. Oncogene. 2005;24(37):5764–74.

    Article  PubMed  CAS  Google Scholar 

  49. Zeisberg M, Yang C, Martino M, et al. Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J Biol Chem. 2007;282(32):23337–47.

    Article  PubMed  CAS  Google Scholar 

  50. Sackett SD, Li Z, Hurtt R, et al. Foxl1 is a marker of bipotential hepatic progenitor cells in mice. Hepatology. 2009;49(3):920–9.

    Article  PubMed  CAS  Google Scholar 

  51. Omenetti A, Porrello A, Jung Y, et al. Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans. J Clin Invest. 2008;118(10):3331–42.

    PubMed  CAS  Google Scholar 

  52. Rygiel KA, Robertson H, Marshall HL, et al. Epithelial-mesenchymal transition contributes to portal tract fibrogenesis during human chronic liver disease. Lab Invest. 2008;88(2):112–23.

    Article  PubMed  CAS  Google Scholar 

  53. Jelnes P, Santoni-Rugiu E, Rasmussen M, et al. Remarkable heterogeneity displayed by oval cells in rat and mouse models of stem cell-mediated liver regeneration. Hepatology. 2007;45(6):1462–70.

    Article  PubMed  CAS  Google Scholar 

  54. Soto-Gutierrez A, Navarro-Alvarez N, Yagi H, Yarmush ML. Stem cells for liver repopulation. Curr Opin Organ Transplant. 2009;14:667–73.

    Article  PubMed  Google Scholar 

  55. Wang X, Willenbring H, Akkari Y, et al. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature. 2003;422(6934):897–901.

    Article  PubMed  CAS  Google Scholar 

  56. Jang YY, Collector MI, Baylin SB, Diehl AM, Sharkis SJ. Hematopoietic stem cells convert into liver cells within days without fusion. Nat Cell Biol. 2004;6(6):532–9.

    Article  PubMed  CAS  Google Scholar 

  57. Banas A, Teratani T, Yamamoto Y, et al. Adipose tissue-derived mesenchymal stem cells as a source of human hepatocytes. Hepatology. 2007;46(1):219–28.

    Article  PubMed  CAS  Google Scholar 

  58. Yagi H, Parekkadan B, Suganuma K, et al. Long term superior performance of a stem cell/hepatocyte device for the treatment of acute liver failure. Tissue Eng Part A. 2009;15:3377–88.

    Article  PubMed  CAS  Google Scholar 

  59. Dan YY, Riehle KJ, Lazaro C, et al. Isolation of multipotent progenitor cells from human fetal liver capable of differentiating into liver and mesenchymal lineages. Proc Natl Acad Sci U S A. 2006;103(26):9912–7.

    Article  PubMed  CAS  Google Scholar 

  60. Oertel M, Menthena A, Chen YQ, Shafritz DA. Properties of cryopreserved fetal liver stem/progenitor cells that exhibit long-term repopulation of the normal rat liver. Stem Cells. 2006;24(10):2244–51.

    Article  PubMed  Google Scholar 

  61. Oertel M, Menthena A, Dabeva MD, Shafritz DA. Cell competition leads to a high level of normal liver reconstitution by transplanted fetal liver stem/progenitor cells. Gastroenterology. 2006;130(2):507–20; quiz 590.

    Google Scholar 

  62. Shafritz DA, Oertel M, Menthena A, Nierhoff D, Dabeva MD. Liver stem cells and prospects for liver reconstitution by transplanted cells. Hepatology. 2006;43(2 Suppl 1):S89–98.

    Article  PubMed  CAS  Google Scholar 

  63. Fox IJ, Roy-Chowdhury J. Hepatocyte transplantation. J Hepatol. 2004;40(6):878–86.

    Article  PubMed  CAS  Google Scholar 

  64. Rao MS, Khan AA, Parveen N, Habeeb MA, Habibullah CM, Pande G. Characterization of hepatic progenitors from human fetal liver during second trimester. World J Gastroenterol. 2008;14(37):5730–7.

    Article  PubMed  Google Scholar 

  65. Khan AA, Parveen N, Mahaboob VS, et al. Management of hyperbilirubinemia in biliary atresia by hepatic progenitor cell transplantation through hepatic artery: a case report. Transplant Proc. 2008;40(4):1153–5.

    Article  PubMed  CAS  Google Scholar 

  66. Basma H, Soto-Gutierrez A, Yannam GR, et al. Differentiation and transplantation of human embryonic stem cell-derived hepatocytes. Gastroenterology. 2009;136(3):990–9.

    Article  PubMed  CAS  Google Scholar 

  67. Soto-Gutierrez A, Kobayashi N, Rivas-Carrillo JD, et al. Reversal of mouse hepatic failure using an implanted liver-assist device containing ES cell-derived hepatocytes. Nat Biotechnol. 2006;24(11):1412–9.

    Article  PubMed  CAS  Google Scholar 

  68. 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(4):335–41.

    Article  PubMed  Google Scholar 

  69. Yamanaka S. Elite and stochastic models for induced pluripotent stem cell generation. Nature. 2009;460(7251):49–52.

    Article  PubMed  CAS  Google Scholar 

  70. Totsugawa T, Yong C, Rivas-Carrillo JD, et al. Survival of liver failure pigs by transplantation of reversibly immortalized human hepatocytes with tamoxifen-mediated self-recombination. J Hepatol. 2007;47(1):74–82.

    Article  PubMed  CAS  Google Scholar 

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Soto-Gutierrez, A., Navarro-Alvarez, N., Kobayashi, N. (2011). Hepatocytes. In: Monga, S. (eds) Molecular Pathology of Liver Diseases. Molecular Pathology Library, vol 5. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-7107-4_3

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  • DOI: https://doi.org/10.1007/978-1-4419-7107-4_3

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