Stem Cell Biology: New Applications for Studying Metabolic Diseases

  • Malte Sgodda
  • Reto Eggenschwiler
  • Tobias Cantz
Conference paper
Part of the ESACT Proceedings book series (ESACT, volume 5)

Abstract

Gaining insights into the biology of human stem cells and into the early embryonic development opens new avenues for generating tissue-specific cells from embryonic stem cells or other pluripotent stem cell sources. With respect to metabolic liver diseases, recent advances in understanding endodermal specification during gastrulation of the post-implantation embryo and in understanding the formation of the hepato-biliary system have strong impact on improved protocols to generate stem cell-derived hepatic cells. The landmark studies from Shinya Yamanaka and co-workers opened a new era in stem cell biology, by providing a technology that allows the generation of pluripotent stem cells from patients’ cells and, thus, allowing the generation of disease-specific stem cells. Taken together these two major advances in the field of stem cell biology, new approaches for studying metabolic liver diseases in correlation to individual patient’s symptoms are available, which provide a breakthrough in new drug target research or individual gene-therapeutic therapies.

Keywords

Hepatic Cell Pluripotent Stem Cell Stem Cell Biology Definitive Endoderm Hepatocyte Transplantation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

The authors are very grateful to Holm Zaehres and Axel Schambach for generation of and support with viral constructs and to Martina Bleidißel and Francoise André for excellent technical assistance. Parts of this work were funded by the Federal Ministry of Education and Research through grants 01GN0812 and 01GM0854. For request concerning detailed information on material and methods, please contact the corresponding author.

References

  1. Agarwal S, Holton, KL, and Lanza, R (2008) Efficient differentiation of functional hepatocytes from human embryonic stem cells. Stem Cells 26: 1117–1127PubMedCrossRefGoogle Scholar
  2. Aurich H, Sgodda, M, Kaltwasser, P, Vetter, M, Weise, A, Liehr, T, Brulport, M, Hengstler, JG, Dollinger, MM, Fleig, WE, and Christ, B (2009) Hepatocyte differentiation of mesenchymal stem cells from human adipose tissue in vitro promotes hepatic integration in vivo. Gut 58: 570–581PubMedCrossRefGoogle Scholar
  3. Buehr M, Meek, S, Blair, K, Yang, J, Ure, J, Silva, J, McLay, R, Hall, J, Ying, QL, and Smith, A (2008) Capture of authentic embryonic stem cells from rat blastocysts. Cell 135: 1287–1298PubMedCrossRefGoogle Scholar
  4. Cai J, Zhao, Y, Liu, Y, Ye, F, Song, Z, Qin, H, Meng, S, Chen, Y, Zhou, R, Song, X, Guo, Y, Ding, M, and Deng, H (2007) Directed differentiation of human embryonic stem cells into functional hepatic cells. Hepatology 45: 1229–1239PubMedCrossRefGoogle Scholar
  5. Cantz T, Manns, MP, and Ott, M (2008) Stem cells in liver regeneration and therapy. Cell Tissue Res 331: 271–282PubMedCrossRefGoogle Scholar
  6. Cantz T, Sharma, AD, Jochheim-Richter, A, Arseniev, L, Klein, C, Manns, MP, and Ott, M (2004) Reevaluation of bone marrow-derived cells as a source for hepatocyte regeneration. Cell Transplantation 13: 659–666PubMedCrossRefGoogle Scholar
  7. Cantz T, Zuckerman, DM, Burda, MR, Dandri, M, Goricke, B, Thalhammer, S, Heckl, WM, Manns, MP, Petersen, J, and Ott, M (2003) Quantitative gene expression analysis reveals transition of fetal liver progenitor cells to mature hepatocytes after transplantation in uPA/RAG-2 mice. Am J Pathol 162: 37–45PubMedCrossRefGoogle Scholar
  8. Cibelli JB, Cunniff, K, and Vrana, KE (2006) Embryonic stem cells from parthenotes. Methods Enzymol 418: 117–135PubMedCrossRefGoogle Scholar
  9. Conrad S, Renninger, M, Hennenlotter, J, Wiesner, T, Just, L, Bonin, M, Aicher, W, Buhring, HJ, Mattheus, U, Mack, A, Wagner, HJ, Minger, S, Matzkies, M, Reppel, M, Hescheler, J, Sievert, KD, Stenzl, A, and Skutella, T (2008) Generation of pluripotent stem cells from adult human testis. Nature 456: 344–349PubMedCrossRefGoogle Scholar
  10. Coronado V, Nanji, M, and Cox, DW (2001) The Jackson toxic milk mouse as a model for copper loading. Mamm Genome 12: 793–795PubMedCrossRefGoogle Scholar
  11. Dhawan A, Mitry, RR, and Hughes, RD (2006) Hepatocyte transplantation for liver-based metabolic disorders. J Inherit Metab Dis 29: 431–435PubMedCrossRefGoogle Scholar
  12. Ek M, Soderdahl, T, Kuppers-Munther, B, Edsbagge, J, Andersson, TB, Bjorquist, P, Cotgreave, I, Jernstrom, B, Ingelman-Sundberg, M, and Johansson, I (2007) Expression of drug metabolizing enzymes in hepatocyte-like cells derived from human embryonic stem cells. Biochem Pharmacol 74: 496–503PubMedCrossRefGoogle Scholar
  13. Evans MJ, and Kaufman, MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292: 154–156PubMedCrossRefGoogle Scholar
  14. Fang B, Shi, M, Liao, L, Yang, S, Liu, Y, and Zhao, RC (2004) Systemic infusion of FLK1(+) mesenchymal stem cells ameliorate carbon tetrachloride-induced liver fibrosis in mice. Transplantation 78: 83–88PubMedCrossRefGoogle Scholar
  15. Fisher RA, and Strom, SC (2006) Human hepatocyte transplantation: worldwide results. Transplantation 82: 441–449PubMedCrossRefGoogle Scholar
  16. Fox IJ, Chowdhury, JR, Kaufman, SS, Goertzen, TC, Chowdhury, NR, Warkentin, PI, Dorko, K, Sauter, BV, and Strom, SC (1998) Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantation. N Engl J Med 338: 1422–1426PubMedCrossRefGoogle Scholar
  17. Gallicano GI, Golestaneh, N, Kokkinaki, M, Pant, D, Jiang, J, Destefano, D, Fernandez-Bueno, C, Rome, JD, Haddad, BR, and Dym, M (2009) Pluripotent stem cells derived from adult human testes. Stem Cells Dev. doi:10.1089/scd.2008.0347Google Scholar
  18. Gouon-Evans V, Boussemart, L, Gadue, P, Nierhoff, D, Koehler, CI, Kubo, A, Shafritz, DA, and Keller, G (2006) BMP-4 is required for hepatic specification of mouse embryonic stem cell-derived definitive endoderm. Nat Biotechnol 24: 1402–1411PubMedCrossRefGoogle Scholar
  19. Grompe M (2006) Principles of therapeutic liver repopulation. J Inherit Metab Dis 29: 421–425PubMedCrossRefGoogle Scholar
  20. Guan K, Nayernia, K, Maier, LS, Wagner, S, Dressel, R, Lee, JH, Nolte, J, Wolf, F, Li, M, Engel, W, and Hasenfuss, G (2006) Pluripotency of spermatogonial stem cells from adult mouse testis. Nature 440: 1199–1203PubMedCrossRefGoogle Scholar
  21. Gupta S, Rajvanshi, P, and Lee, CD (1995) Integration of transplanted hepatocytes into host liver plates demonstrated with dipeptidyl peptidase IV-deficient rats. Proc Natl Acad Sci USA 92: 5860–5864PubMedCrossRefGoogle Scholar
  22. Gupta S, Rajvanshi, P, Sokhi, R, Slehria, S, Yam, A, Kerr, A, and Novikoff, PM (1999) Entry and integration of transplanted hepatocytes in rat liver plates occur by disruption of hepatic sinusoidal endothelium. Hepatology 29: 509–519PubMedCrossRefGoogle Scholar
  23. Hamazaki T, Iiboshi, Y, Oka, M, Papst, PJ, Meacham, AM, Zon, LI, and Terada, N (2001) Hepatic maturation in differentiating embryonic stem cells in vitro. FEBS Lett 497: 15–19PubMedCrossRefGoogle Scholar
  24. Hanna J, Wernig, M, Markoulaki, S, Sun, CW, Meissner, A, Cassady, JP, Beard, C, Brambrink, T, Wu, LC, Townes, TM, and Jaenisch, R (2007) Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 318: 1920–1923PubMedCrossRefGoogle Scholar
  25. Hansson M, Olesen, DR, Peterslund, JM, Engberg, N, Kahn, M, Winzi, M, Klein, T, Maddox-Hyttel, P, and Serup, P (2009) A late requirement for Wnt and FGF signaling during activin-induced formation of foregut endoderm from mouse embryonic stem cells. Dev Biol 330: 286–304PubMedCrossRefGoogle Scholar
  26. Haridass D, Yuan, Q, Becker, PD, Cantz, T, Iken, M, Rothe, M, Narain, N, Bock, M, Norder, M, Legrand, N, Wedemeyer, H, Weijer, K, Spits, H, Manns, MP, Cai, J, Deng, H, Di Santo, JP, Guzman, CA, and Ott, M (2009) Repopulation efficiencies of adult hepatocytes, fetal liver progenitor cells, and embryonic stem cell-derived hepatic cells in albumin-promoter-enhancer urokinase-type plasminogen activator mice. Am J Pathol. doi:10.2353/ajpath.2009.090117Google Scholar
  27. Hay DC, Zhao, D, Ross, A, Mandalam, R, Lebkowski, J, and Cui, W (2007) Direct differentiation of human embryonic stem cells to hepatocyte-like cells exhibiting functional activities. Cloning Stem Cells 9: 51–62PubMedCrossRefGoogle Scholar
  28. Heo J, Factor, VM, Uren, T, Takahama, Y, Lee, JS, Major, M, Feinstone, SM, and Thorgeirsson, SS (2006) Hepatic precursors derived from murine embryonic stem cells contribute to regeneration of injured liver. Hepatology 44: 1478–1486PubMedCrossRefGoogle Scholar
  29. Herzog EL, Chai, L, and Krause, DS (2003) Plasticity of marrow-derived stem cells. Blood 102: 3483–3493PubMedCrossRefGoogle Scholar
  30. Jochheim A, Hillemann, T, Kania, G, Scharf, J, Attaran, M, Manns, MP, Wobus, AM, and Ott, M (2004) Quantitative gene expression profiling reveals a fetal hepatic phenotype of murine ES-derived hepatocytes. Int J Dev Biol 48: 23–29PubMedCrossRefGoogle Scholar
  31. Kanatsu-Shinohara M, Inoue, K, Lee, J, Yoshimoto, M, Ogonuki, N, Miki, H, Baba, S, Kato, T, Kazuki, Y, Toyokuni, S, Toyoshima, M, Niwa, O, Oshimura, M, Heike, T, Nakahata, T, Ishino, F, Ogura, A, and Shinohara, T (2004) Generation of pluripotent stem cells from neonatal mouse testis. Cell 119: 1001–1012PubMedCrossRefGoogle Scholar
  32. Kanazawa Y, and Verma, IM (2003) Little evidence of bone marrow-derived hepatocytes in the replacement of injured liver. Proc Natl Acad Sci USA 100 Suppl 1: 11850–11853CrossRefGoogle Scholar
  33. Kania G, Blyszczuk, P, Jochheim, A, Ott, M, and Wobus, AM (2004) Generation of glycogen- and albumin-producing hepatocyte-like cells from embryonic stem cells. Biol Chem 385: 943–953PubMedCrossRefGoogle Scholar
  34. Kim K, Lerou, P, Yabuuchi, A, Lengerke, C, Ng, K, West, J, Kirby, A, Daly, MJ, and Daley, GQ (2007a) Histocompatible embryonic stem cells by parthenogenesis. Science 315: 482–486PubMedCrossRefGoogle Scholar
  35. Kim K, Ng, K, Rugg-Gunn, PJ, Shieh, JH, Kirak, O, Jaenisch, R, Wakayama, T, Moore, MA, Pedersen, RA, and Daley, GQ (2007b) Recombination signatures distinguish embryonic stem cells derived by parthenogenesis and somatic cell nuclear transfer. Cell Stem Cell 1: 346–352PubMedCrossRefGoogle Scholar
  36. Kim JB, Zaehres, H, Wu, G, Gentile, L, Ko, K, Sebastiano, V, Arauzo-Bravo, MJ, Ruau, D, Han, DW, Zenke, M, and Scholer, HR (2008) Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors. Nature 454: 646–650PubMedCrossRefGoogle Scholar
  37. Ko K, Tapia, N, Wu, G, Kim, JB, Arauzo-Bravo, MJ, Sasse, P, Glaser, T, Ruau, D, Han, DW, Greber, B, Hausdörfer, K, Sebastiano, V, Stehling, M, Fleischmann, BK, Brüstle, O, Zenke, M, and Schöler, HR (2009) Induction of pluripotency in adult unipotent germline stem cells. Cell Stem Cell 5: 87–96PubMedCrossRefGoogle Scholar
  38. Kriegeskotte C, Cantz, T, Haberland, J, Zibert, A, Haier, J, Kohler, G, Scholer, HR, Schmidt, HH, and Arlinghaus, HF (2009) Laser secondary neutral mass spectrometry for copper detection in micro-scale biopsies. J Mass Spectrom 44: 1417–1422PubMedCrossRefGoogle Scholar
  39. Lysy PA, Campard, D, Smets, F, Najimi, M, and Sokal, EM (2008) Stem cells for liver tissue repair: current knowledge and perspectives. World J Gastroenterol 14: 864–875PubMedCrossRefGoogle Scholar
  40. Maherali N, Sridhara, R, Wei, X, Utikal, J, Eminli, S, Arnold, K, Stadtfeld, M, Yachechko, R, Tchieu, J, Jaenisch, R, Plath, K, and Hochedlinger, K (2007) Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell 1: 55–70PubMedCrossRefGoogle Scholar
  41. Meissner A, Wernig, M, and Jaenisch, R (2007) Direct reprogramming of genetically unmodified fibroblasts into pluripotent stem cells. Nat Biotechnol 25: 1177–1181PubMedCrossRefGoogle Scholar
  42. Najimi M, and Sokal, E (2005) Liver cell transplantation. Minerva Pediatr 57: 243–257PubMedGoogle Scholar
  43. Oertel M, and Shafritz, DA (2008) Stem cells, cell transplantation and liver repopulation. Biochim Biophys Acta 1782: 61–74PubMedGoogle Scholar
  44. Okita K, Ichisaka, T, and Yamanaka, S (2007) Generation of germline-competent induced pluripotent stem cells. Nature 448: 313–317PubMedCrossRefGoogle Scholar
  45. Park IH, Zhao, R, West, JA, Yabuuchi, A, Huo, H, Ince, TA, Lerou, PH, Lensch, MW, and Daley, GQ (2008) Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451: 141–146PubMedCrossRefGoogle Scholar
  46. Rathjen J, and Rathjen, PD (2001) Mouse ES cells: experimental exploitation of pluripotent differentiation potential. Curr Opin Genet Dev 11: 587–594PubMedCrossRefGoogle Scholar
  47. Raya A, Rodriguez-Piza, I, Guenechea, G, Vassena, R, Navarro, S, Barrero, MJ, Consiglio, A, Castella, M, Rio, P, Sleep, E, Gonzalez, F, Tiscornia, G, Garreta, E, Aasen, T, Veiga, A, Verma, IM, Surralles, J, Bueren, J, and Izpisua Belmonte, JC (2009) Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature 460: 53–59PubMedCrossRefGoogle Scholar
  48. Sandhu JS, Petkov, PM, Dabeva, MD, and Shafritz, DA (2001) Stem cell properties and repopulation of the rat liver by fetal liver epithelial progenitor cells. Am J Pathol 159: 1323–1334PubMedCrossRefGoogle Scholar
  49. Schneider A, Attaran, M, Meier, PN, Strassburg, C, Manns, MP, Ott, M, Barthold, M, Arseniev, L, Becker, T, and Panning, B (2006) Hepatocyte transplantation in an acute liver failure due to mushroom poisoning. Transplantation 82: 1115–1116PubMedCrossRefGoogle Scholar
  50. Schwartz RE, Reyes, M, Koodie, L, Jiang, Y, Blackstad, M, Lund, T, Lenvik, T, Johnson, S, Hu, WS, and Verfaillie, CM (2002) Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J Clin Invest 109: 1291–1302PubMedGoogle Scholar
  51. Seandel M, James, D, Shmelkov, SV, Falciatori, I, Kim, J, Chavala, S, Scherr, DS, Zhang, F, Torres, R, Gale, NW, Yancopoulos, GD, Murphy, A, Valenzuela, DM, Hobbs, RM, Pandolfi, PP, and Rafii, S (2007) Generation of functional multipotent adult stem cells from GPR125+ germline progenitors. Nature 449: 346–350PubMedCrossRefGoogle Scholar
  52. Sgodda M, Aurich, H, Kleist, S, Aurich, I, Konig, S, Dollinger, MM, Fleig, WE, and Christ, B (2007) Hepatocyte differentiation of mesenchymal stem cells from rat peritoneal adipose tissue in vitro and in vivo. Exp Cell Res 313: 2875–2886PubMedCrossRefGoogle Scholar
  53. Sharma AD, Cantz, T, Vogel, A, Schambach, A, Haridass, D, Iken, M, Bleidissel, M, Manns, MP, Scholer, HR, and Ott, M (2008) Murine embryonic stem cell-derived hepatic progenitor cells engraft in recipient livers with limited capacity of liver tissue formation. Cell Transplant 17: 313–323PubMedCrossRefGoogle Scholar
  54. Stephenne X, Vosters, O, Najimi, M, Beuneu, C, Dung, KN, Wijns, W, Goldman, M, and Sokal, EM (2007) Tissue factor-dependent procoagulant activity of isolated human hepatocytes: relevance to liver cell transplantation. Liver Transpl 13: 599–606PubMedCrossRefGoogle Scholar
  55. Strick-Marchand H, Morosan, S, Charneau, P, Kremsdorf, D, and Weiss, MC (2004) Bipotential mouse embryonic liver stem cell lines contribute to liver regeneration and differentiate as bile ducts and hepatocytes. Proc Natl Acad Sci USA 101: 8360–8365PubMedCrossRefGoogle Scholar
  56. Takahashi K, Tanabe, K, Ohnuki, M, Narita, M, Ichisaka, T, Tomoda, K, and Yamanaka, S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131: 861–872PubMedCrossRefGoogle Scholar
  57. Takahashi K, and Yamanaka, S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126: 663–676PubMedCrossRefGoogle Scholar
  58. Theise ND, Badve, S, Saxena, R, Henegariu, O, Sell, S, Crawford, JM, and Krause, DS (2000a) Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation. Hepatology 31: 235–240PubMedCrossRefGoogle Scholar
  59. Theise ND, Nimmakayalu, M, Gardner, R, Illei, PB, Morgan, G, Teperman, L, Henegariu, O, and Krause, DS (2000b) Liver from bone marrow in humans. Hepatology 32: 11–16PubMedCrossRefGoogle Scholar
  60. Thomson JA, Itskovitz-Eldor, J, Shapiro, SS, Waknitz, MA, Swiergiel, JJ, Marshall, VS, and Jones, JM (1998) Embryonic stem cell lines derived from human blastocysts. Science 282: 1145–1147PubMedCrossRefGoogle Scholar
  61. Thomson JA, Kalishman, J, Golos, TG, Durning, M, Harris, CP, Becker, RA, and Hearn, JP (1995) Isolation of a primate embryonic stem cell line. Proc Natl Acad Sci USA 92: 7844–7848PubMedCrossRefGoogle Scholar
  62. Thomson JA, Kalishman, J, Golos, TG, Durning, M, Harris, CP, and Hearn, JP (1996) Pluripotent cell lines derived from common marmoset (Callithrix jacchus) blastocysts. Biol Reprod 55: 254–259PubMedCrossRefGoogle Scholar
  63. Wagers AJ, Sherwood, RI, Christensen, JL, and Weissman, IL (2002) Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 297: 2256–2259PubMedCrossRefGoogle Scholar
  64. Weglarz TC, Degen, JL, and Sandgren, EP (2000) Hepatocyte transplantation into diseased mouse liver. Kinetics of parenchymal repopulation and identification of the proliferative capacity of tetraploid and octaploid hepatocytes. Am J Pathol 157: 1963–1974PubMedCrossRefGoogle Scholar
  65. Willenbring H, Bailey, AS, Foster, M, Akkari, Y, Dorrell, C, Olson, S, Finegold, M, Fleming, WH, and Grompe, M (2004) Myelomonocytic cells are sufficient for therapeutic cell fusion in liver. Nat Med 10: 744–748PubMedCrossRefGoogle Scholar
  66. Yu J, Vodyanik, MA, Smuga-Otto, K, Antosiewicz-Bourget, J, Frane, JL, Tian, S, Nie, J, Jonsdottir, GA, Ruotti, V, Stewart, R, Slukvin, II, and Thomson, JA (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318: 1917–1920PubMedCrossRefGoogle Scholar
  67. Zaret KS, and Grompe, M (2008) Generation and regeneration of cells of the liver and pancreas. Science 322: 1490–1494PubMedCrossRefGoogle Scholar
  68. Zhao DC, Lei, JX, Chen, R, Yu, WH, Zhang, XM, Li, SN, and Xiang, P (2005) Bone marrow-derived mesenchymal stem cells protect against experimental liver fibrosis in rats. World J Gastroenterol 11: 3431–3440PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Malte Sgodda
    • 1
  • Reto Eggenschwiler
    • 1
  • Tobias Cantz
    • 1
  1. 1.Stem Cell Biology, Cluster-of-Excellence “REBIRTH”Hannover Medical SchoolHanoverGermany

Personalised recommendations