Surgery Today

, 39:1019 | Cite as

Potentials of regenerative medicine for liver disease

  • Shinichiro Ogawa
  • Shinichi Miyagawa
Review Article

Abstract

Liver transplantation is still the only effective treatment for end-stage liver disease. However, because of the serious worldwide shortage of donated organs, an alternative cellular therapy would be desirable. Animal studies and preclinical trials have indicated that hepatocyte transplantation can serve as an alternative to liver transplantation. Unfortunately, however, the harvesting of hepatocytes is associated with the same problem as organ transplantation, i.e., a lack of a suitable cell source. Therefore, current stem cell technology, which is attempting to establish an unlimited supply of hepatocytes, would facilitate the clinical application of hepatocyte transplantation. This review summarizes current knowledge of embryonic and adult stem cell differentiation into hepatocytes and discusses how liver stem cells could be applied clinically in the future.

Key words

Liver transplantation Hepatocyte Stem cell Cellular therapy 

References

  1. 1.
    Farber E. Carcinoma of the liver in rats fed ethionine. AMA Arch Pathol 1956;62:445–453.PubMedGoogle Scholar
  2. 2.
    Evarts RP, Nagy P, Marsden E, Thorgeirsson SS. A precursor-product relationship exists between oval cells and hepatocytes in rat liver. Carcinogenesis 1987;8:1737–1740.CrossRefPubMedGoogle Scholar
  3. 3.
    Theise ND, Saxena R, Portmann BC, Thung SN, Yee H, Chiriboga L, et al. The canals of Hering and hepatic stem cells in humans. Hepatology 1999;30:1425–1433.CrossRefPubMedGoogle Scholar
  4. 4.
    Popper H, Kent G, Stein R. Ductular cell reaction in the liver in hepatic injury. J Mount Sinai Hosp 1957;24:551–556.Google Scholar
  5. 5.
    Gerber MA, Thung SN. Liver stem cells and development. Lab Invest 1993;68:253–254.PubMedGoogle Scholar
  6. 6.
    Roskams TA, Theise ND, Balabaud C, Bhagat G, Bhathal PS, Bioulac-Sage P, et al. Nomenclature of the finer branches of the biliary tree: canals, ductules, and ductular reactions in human livers. Hepatology 2004;39:1739–1745.CrossRefPubMedGoogle Scholar
  7. 7.
    Petersen BE, Goff JP, Greenberger JS, Michalopoulos GK. Hepatic oval cells express the hematopoietic stem cell marker Thy-1 in the rat. Hepatology 1998;27:433–445.CrossRefPubMedGoogle Scholar
  8. 8.
    Crosby HA, Kelly DA, Strain AJ. Human hepatic stem-like cells isolated using c-kit or CD34 can differentiate into biliary epithelium. Gastroenterology 2001;120:534–544.CrossRefPubMedGoogle Scholar
  9. 9.
    Petersen BE, Grossbard B, Hatch H, Pi L, Deng J, Scott EW. Mouse A6-positive hepatic oval cells also express several hematopoietic stem cell markers. Hepatology 2003;37:632–640.CrossRefPubMedGoogle Scholar
  10. 10.
    Petersen BE, Bowen WC, Patrene KD, Mars WM, Sullivan AK, Murase N, et al. Bone marrow as a potential source of hepatic oval cells. Science 1999;284:1168–1170.CrossRefPubMedGoogle Scholar
  11. 11.
    Wang X, Foster M, Al-Dhalimy M, Lagasse E, Finegold M, Grompe M. The origin and liver repopulating capacity of murine oval cells. Proc Natl Acad Sci USA 2003;100suppl 1:11881–11888.CrossRefPubMedGoogle Scholar
  12. 12.
    Kubota K, Soeda J, Misawa R, Mihara M, Miwa S, Ise H, et al. Bone marrow-derived cells fuse with hepatic oval cells but are not involved in hepatic tumorigenesis in the choline-deficient ethionine-supplemented diet rat model. Carcinogenesis 2008;29:448–454.CrossRefPubMedGoogle Scholar
  13. 13.
    Menthena A, Deb N, Oertel M, Grozdanova PN, Sandhua J, Shahb S, et al. Bone marrow progenitors are not the source of expanding oval cells in injured liver. Stem Cells 2004;22:1049–1061.CrossRefPubMedGoogle Scholar
  14. 14.
    Thorgeirsson SS, Grisham JW. Hematopoietic cells as hepatocyte stem cells: a critical review of the evidence. Hepatology 2006;43:2–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Shiojiri N, Lemire JM, Fausto N. Cell lineages and oval cell progenitors in rat liver development. Cancer Res 1991;51:2611–2620.PubMedGoogle Scholar
  16. 16.
    Germain L, Blouin MJ, Marceau N. Biliary epithelial and hepatocytic cell lineage relationships in embryonic rat liver as determined by the differential expression of cytokeratins, alphafetoprotein, albumin, and cell surface-exposed components. Cancer Res 1988;48:4909–4918.PubMedGoogle Scholar
  17. 17.
    Rogler LE. Selective bipotential differentiation of mouse embryonic hepatoblasts in vitro. Am J Pathol 1997;150:591–602.PubMedGoogle Scholar
  18. 18.
    Suzuki A, Zheng Y, Kondo R, Kusakabe M, Takada Y, Fukao K, et al. Flow-cytometric separation and enrichment of hepatic progenitor cells in the developing mouse liver. Hepatology 2000;32:1230–1239.CrossRefPubMedGoogle Scholar
  19. 19.
    Tanimizu N, Nishikawa M, Saito H, Tsujimura T, Miyajima A. Isolation of hepatoblasts based on the expression of Dlk/Pref-1. J Cell Sc 2003;116:1775–1786.CrossRefGoogle Scholar
  20. 20.
    Tanimizu N, Saito H, Mostov K, Miyajima A. Long-term culture of hepatic progenitors derived from mouse Dlk+ hepatoblasts. J Cell Sci 2004;117:6425–6434.CrossRefPubMedGoogle Scholar
  21. 21.
    Nierhoff D, Ogawa A, Oertel M, Chen YQ, Shafritz DA. Purification and characterization of mouse fetal liver epithelial cells with high in vivo repopulation capacity. Hepatology 2005;42:130–139.CrossRefPubMedGoogle Scholar
  22. 22.
    Oertel M, Menthena A, Chen YQ, Teisner B, Jensen CH, Shafritz DA. Purification of fetal liver stem/progenitor cells containing all the repopulation potential for normal adult rat liver. Gastroenterology 2008;134:823–832.PubMedGoogle Scholar
  23. 23.
    Theise ND, Nimmakayalu M, Gardner R, Illei PB, Morgan G, Teperman L, et al. Liver from bone marrow in humans. Hepatology 2000;32:11–16.CrossRefPubMedGoogle Scholar
  24. 24.
    Körbling M, Katz RL, Khanna A, Ruifrok AC, Rondon G, Albitar M, et al. Hepatocytes and epithelial cells of donor origin in recipients of peripheral-blood stem cells. N Engl J M 2002;346:738–746.CrossRefGoogle Scholar
  25. 25.
    Alison MR, Poulsom R, Jeffery R, Dhillon AP, Quaglia A, Jacob J, et al. Hepatocytes from non-hepatic adult stem cells. Nature 2000;406:257.CrossRefPubMedGoogle Scholar
  26. 26.
    Idilman R, Erden E, Kuzu I, Ersoz S, Karayalcin S. The fate of recipient-derived hepatocytes in sex-mismatched liver allograft following liver transplantation. Clin Transpl 2007;21:202–206.CrossRefGoogle Scholar
  27. 27.
    Lagasse E, Connors H, Al-Dhalimy M, Reitsma M, Dohse M, Osborne L, et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med 2000;6:1229–1234.CrossRefPubMedGoogle Scholar
  28. 28.
    Willenbring H, Bailey AS, Foster M, Akkari Y, Dorrell C, Olson S, et al. Myelomonocytic cells are sufficient for therapeutic cell fusion in liver. Nat Med 2004;10:744–748.CrossRefPubMedGoogle Scholar
  29. 29.
    Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, Fike JR, Lee HO, Pfeffer K, et al. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 2003;425:968–973.CrossRefPubMedGoogle Scholar
  30. 30.
    Cantz T, Sharma AD, Jochheim-Richter A, Arseniev L, Klein C, Manns MP, et al. Reevaluation of bone marrow-derived cells as a source for hepatocyte regeneration. Cell Transpl 2004;13:659–666.CrossRefGoogle Scholar
  31. 31.
    Kanazawa Y, Verma IM. Little evidence of bone marrow-derived hepatocytes in the replacement of injured liver. Proc Natl Acad Sci USA 2003;100 suppl 1:11850–11853.CrossRefGoogle Scholar
  32. 32.
    Mitchell C, Fausto N. Bone marrow-derived hepatocytes: rare but promising. Am J Pathol 2002;161:349–350.PubMedGoogle Scholar
  33. 33.
    Harris RG, Herzog EL, Bruscia EM, Grove JE, Van Arnam JS, Krause DS. Lack of a fusion requirement for development of bone marrow-derived epithelia. Science 2004;305:90–93.CrossRefPubMedGoogle Scholar
  34. 34.
    Misawa R, Ise H, Takahashi M, Morimoto H, Kobayashi E, Miyagawa S, et al. Development of liver regenerative therapy using glycoside-modified bone marrow cells. Biochem Biophys Res Commun 2006;342:434–440.CrossRefPubMedGoogle Scholar
  35. 35.
    Muraca M, Ferraresso C, Vilei MT, Granato A, Quarta M, Cozzi E, et al. Liver repopulation with bone marrow derived cells improves the metabolic disorder in the Gunn rat. Gut 2007;56:1725–1735.CrossRefPubMedGoogle Scholar
  36. 36.
    am Esch JS 2nd, Knoefel WT, Klein M, Ghodsizad A, Fuerst G, Poll LW, et al. Portal application of autologous CD133+ bone marrow cells to the liver: a novel concept to support hepatic regeneration. Stem Cells 2005;23:463–470.CrossRefPubMedGoogle Scholar
  37. 37.
    Fürst G, Schulte am Esch J, Poll LW, Hosch SB, Fritz LB, Klein M, et al. Portal vein embolization and autologous CD133+ bone marrow stem cells for liver regeneration: initial experience. Radiology 2007;243:171–179.CrossRefPubMedGoogle Scholar
  38. 38.
    Kuo TK, Hung SP, Chuang CH, Chen CT, Shih YR, Fang SC, et al. Stem cell therapy for liver disease: parameters governing the success of using bone marrow mesenchymal stem cells. Gastroenterology 2008;134:2111–2121.CrossRefPubMedGoogle Scholar
  39. 39.
    Carvalho AB, Quintanilha LF, Dias JV, Paredesa BD, Mannheimera EG, Carvalhob FG, et al. Bone marrow multipotent mesenchymal stromal cells do not reduce fibrosis or improve function in a rat model of severe chronic liver injury. Stem Cells 2008;26:1307–1314.CrossRefPubMedGoogle Scholar
  40. 40.
    Hamazaki T, Iiboshi Y, Oka M, Papst PJ, Meacham AM, Zon LI, et al. Hepatic maturation in differentiating embryonic stem cells in vitro. FEBS Lett 2001;497:15–19.CrossRefPubMedGoogle Scholar
  41. 41.
    Yamada T, Yoshikawa M, Kanda S, Kato Y, Nakajima Y, Ishizaka S, et al. In vitro differentiation of embryonic stem cells into hepatocyte-like cells identified by cellular uptake of indocyanine green. Stem Cells 2002;20:146–154.CrossRefPubMedGoogle Scholar
  42. 42.
    Kuai XL, Cong XQ, Li XL, Xiao SD. Generation of hepatocytes from cultured mouse embryonic stem cells. Liver Transpl 2003;9:1094–1099.CrossRefPubMedGoogle Scholar
  43. 43.
    Yamamoto H, Quinn G, Asari A, Yamanokuchi H, Teratani T, Terada M, et al. Differentiation of embryonic stem cells into hepatocytes: biological functions and therapeutic application. Hepatology 2003;37:983–993.CrossRefPubMedGoogle Scholar
  44. 44.
    Kubo A, Shinozaki K, Shannon JM, Kouskoff V, Kennedy M, Woo S, et al. Development of definitive endoderm from embryonic stem cells in culture. Development 2004;131:1651–1662.CrossRefPubMedGoogle Scholar
  45. 45.
    Gouon-Evans V, Boussemart L, Gadue P, Nierhoff D, Koehler CI, Kubo A, et al. BMP-4 is required for hepatic specification of mouse embryonic stem cell-derived definitive endoderm. Nat Biotechnol 2006;24:1402–1411.CrossRefPubMedGoogle Scholar
  46. 46.
    Soto-Gutiérrez A, Kobayashi N, Rivas-Carrillo JD, Navarro-Alvarez N, Zhao D, Okitsu T, et al. Reversal of mouse hepatic failure using an implanted liver-assist device containing ES cell-derived hepatocytes. Nat Biotechnol 2006;24:1412–1419.CrossRefPubMedGoogle Scholar
  47. 47.
    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;23:1534–1541.CrossRefPubMedGoogle Scholar
  48. 48.
    Lavon N, Yanuka O, Benvenisty N. Differentiation and isolation of hepatic-like cells from human embryonic stem cells. Differentiation 2004;72:230–238.CrossRefPubMedGoogle Scholar
  49. 49.
    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;14:643–655.CrossRefPubMedGoogle Scholar
  50. 50.
    Cai J, Zhao Y, Liu Y, Ye F, Song Z, Qin H, et al. Directed differentiation of human embryonic stem cells into functional hepatic cells. Hepatology 2007;45:1229–1239.CrossRefPubMedGoogle Scholar
  51. 51.
    Duan Y, Catana A, Meng Y, Yamamoto N, He S, Gupta S, et al. Differentiation and enrichment of hepatocyte-like cells from human embryonic stem cells in vitro and in vivo. Stem Cells 2007;25:3058–3068.CrossRefPubMedGoogle Scholar
  52. 52.
    Rambhatla L, Chiu CP, Kundu P, Peng Y, Carpenter MK. Generation of hepatocyte-like cells from human embryonic stem cells. Cell Transpl 2003;12:1–11.CrossRefGoogle Scholar
  53. 53.
    Hay DC, Zhao D, Ross A, Mandalam R, Lebkowski J, Cui W. Direct differentiation of human embryonic stem cells to hepatocyte-like cells exhibiting functional activities. Cloning Stem Cells 2007;9:51–62.CrossRefPubMedGoogle Scholar
  54. 54.
    Hay DC, Zhao D, Fletcher J, Hewitt ZA, McLean D, Urruticoechea-Uriguen A, et al. Efficient differentiation of hepatocytes from human embryonic stem cells exhibiting markers recapitulating liver development in vivo. Stem Cells 2008;26:894–902.CrossRefPubMedGoogle Scholar
  55. 55.
    Horiuchi K, Fujimoto D, Fukushima M, Kanai K. Increased histone acetylation and deacetylation in rat ascites hepatoma cells. Cancer Res 1981;41:1488–1491.PubMedGoogle Scholar
  56. 56.
    Saito H, Morizane T, Watanabe T, Kagawa T, Miyaguchi S, Kumagai N, et al. Differentiating effect of sodium butyrate on human hepatoma cell lines PLC/PRF/5, HCC-M and HCC-T. Int J Cancer 1991;48:291–296.CrossRefPubMedGoogle Scholar
  57. 57.
    Yoon JH, Lee HV, Lee JS, Park JB, Kim CY. Development of a non-transformed human liver cell line with differentiatedhepatocyte and urea-synthetic functions: applicable for bioartificial liver. Int J Artif Organs 1999;22:769–777.PubMedGoogle Scholar
  58. 58.
    Basma H, Soto-Gutiérrez A, Yannam GR, Liu L, Ito R, Yamamoto T, et al. Differentiation and transplantation of human embryonic stem cell-derived hepatocytes. Gastroenterology 2009;136:990–999.CrossRefPubMedGoogle Scholar
  59. 59.
    Samlowski WE, Daynes RA. Bone marrow engraftment efficiency is enhanced by competitive inhibition of the hepatic asialoglycoprotein receptor. Proc Natl Acad Sci USA 1985;82:2508–2512.CrossRefPubMedGoogle Scholar
  60. 60.
    Ogawa S, Tagawa Y, Kamiyoshi A, Suzuki A, Nakayama J, Hashikura Y, et al. Crucial roles of mesodermal cell lineages in a murine embryonic stem cell-derived in vitro liver organogenesis system. Stem Cells 2005;23:903–913.CrossRefPubMedGoogle Scholar
  61. 61.
    Tsutsui M, Ogawa S, Inada Y, Tomioka E, Kamiyoshi A, Tanaka S, et al. Characterization of cytochrome P450 expression in murine embryonic stem cell-derived hepatic tissue system. Drug Metab Dispos 2006;34:696–701.CrossRefPubMedGoogle Scholar
  62. 62.
    Fujimori H, Asahina K, Shimizu-Saito K, Ikeda R, Tanaka Y, Teramoto K, et al. Vascular endothelial growth factor promotes proliferation and function of hepatocyte-like cells in embryoid bodies formed from mouse embryonic stem cells. J Hepatol 2008;48:962–973.CrossRefPubMedGoogle Scholar
  63. 63.
    Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007;131:861–872.CrossRefPubMedGoogle Scholar

Copyright information

© Springer 2009

Authors and Affiliations

  • Shinichiro Ogawa
    • 1
    • 2
  • Shinichi Miyagawa
    • 1
  1. 1.Department of SurgeryShinshu University School of MedicineNaganoJapan
  2. 2.McEwen Centre for Regenerative MedicineUniversity Health NetworkTorontoCanada

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