Hepatology International

, Volume 8, Issue 2, pp 158–165 | Cite as

Cell therapies and regenerative medicine

Review Article


Molecular and cell biology has resulted in major advances in our understanding of disease pathogenesis as well as in novel strategies for the diagnosis, therapy and prevention of human diseases. Based on modern molecular, genetic and biochemical methodologies, it is on the one hand possible to identify disease-related point mutations and single nucleotide polymorphisms, for example. On the other hand, using high throughput array and other technologies, it is for example possible to simultaneously analyze thousands of genes or gene products (RNA and proteins), resulting in an individual gene or gene expression profile (‘signature’). Such data increasingly allow defining the individual disposition for a given disease and predicting disease prognosis as well as the efficacy of therapeutic strategies in the individual patient (‘personalized medicine’). At the same time, the basic discoveries in cell biology, including embryonic and adult stem cells, induced pluripotent stem cells, genetically modified cells and others, have moved regenerative medicine into the center of biomedical research worldwide with a major translational impact on tissue engineering as well as transplantation medicine. All these aspects have greatly contributed to the recent advances in regenerative medicine and the development of novel concepts for the treatment of many human diseases, including liver diseases.


Human Genome Organization (HUGO) Genome-wide association studies (GWAS) Array analyses Stem cells Regenerative medicine Transplantation medicine Personalized medicine 


  1. 1.
    Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, et al. Initial sequencing and analysis of the human genome. Nature 2001;409:860–921PubMedCrossRefGoogle Scholar
  2. 2.
    Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, et al. The sequence of the human genome. Science 2001;291:1304–1351PubMedCrossRefGoogle Scholar
  3. 3.
    The International HapMap Project. Nature 2003;426:789–796.CrossRefGoogle Scholar
  4. 4.
    A haplotype map of the human genome. Nature 2005;437:1299–1320CrossRefGoogle Scholar
  5. 5.
    Manolio TA, Brooks LD, Collins FS. A HapMap harvest of insights into the genetics of common disease. J Clin Invest 2008;118:1590–1605PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Manolio TA, Collins FS. The HapMap and genome-wide association studies in diagnosis and therapy. Annu Rev Med 2009;60:443–456PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Samani NJ, Erdmann J, Hall AS, Hengstenberg C, Mangino M, Mayer B, et al. Genomewide association analysis of coronary artery disease. N Engl J Med 2007;357:443–453PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Rosenzweig A. Scanning the genome for coronary risk. N Engl J Med 2007;357:497–499PubMedCrossRefGoogle Scholar
  9. 9.
    Stefansson H, Rye DB, Hicks A, Petursson H, Ingason A, Thorgeirsson TE, et al. A genetic risk factor for periodic limb movements in sleep. N Engl J Med 2007;357:639–647PubMedCrossRefGoogle Scholar
  10. 10.
    Dunckley T, Huentelman MJ, Craig DW, Pearson JV, Szelinger S, Joshipura K, et al. Whole-genome analysis of sporadic amyotrophic lateral sclerosis. N Engl J Med 2007;357:775–788PubMedCrossRefGoogle Scholar
  11. 11.
    Hafler DA, Compston A, Sawcer S, Lander ES, Daly MJ, De Jager PL, et al. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 2007;357:851–862PubMedCrossRefGoogle Scholar
  12. 12.
    Hirschhorn JN, Gajdos ZK. Genome-wide association studies: results from the first few years and potential implications for clinical medicine. Annu Rev Med 2011;62:11–24PubMedCrossRefGoogle Scholar
  13. 13.
    Petersen KF, Dufour S, Hariri A, Nelson-Williams C, Foo JN, Zhang XM, et al. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J Med 2010;362:1082–1089PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Diepolder HM, Gerlach J-T, Zachoval R, Hoffmann RM, Jung M-C, Wierenga EA, et al. Immunodominant CD4+ T-cell epitope within nonstructural protein 3 in acute hepatitis C virus infection. J Virol 1997;71:6011–6019PubMedCentralPubMedGoogle Scholar
  15. 15.
    Tanabe KK, Lemoine A, Finkelstein DM, Kawasaki H, Fujii T, Chung RT, et al. Epidermal growth factor gene functional polymorphism and the risk of hepatocellular carcinoma in patients with cirrhosis. JAMA 2008;299:53–60PubMedCrossRefGoogle Scholar
  16. 16.
    Wacholder S, Hartge P, Prentice R, Garcia-Closas M, Feigelson HS, Diver WR, et al. Performance of common genetic variants in breast-cancer risk models. N Engl J Med 2010;362:986–993PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Goldstein DB. Common genetic variation and human traits. N Engl J Med 2009;360:1696–1698PubMedCrossRefGoogle Scholar
  18. 18.
    Kraft P, Hunter DJ. Genetic risk prediction—are we there yet? N Engl J Med 2009;360:1701–1703PubMedCrossRefGoogle Scholar
  19. 19.
    Proctor LM. The Human Microbiome Project in 2011 and beyond. Cell Host Microbe 2011;10:287–291PubMedCrossRefGoogle Scholar
  20. 20.
    Spor A, Koren O, Ley R. Unravelling the effects of the environment and host genotype on the gut microbiome. Nat Rev Microbiol 2011;9:279–290PubMedCrossRefGoogle Scholar
  21. 21.
    Human Microbiome Project C. A framework for human microbiome research. Nature 2012;486:215–221CrossRefGoogle Scholar
  22. 22.
    Gevers D, Knight R, Petrosino JF, Huang K, McGuire AL, Birren BW, et al. The Human Microbiome Project: a community resource for the healthy human microbiome. PLoS Biol 2012;10:e1001377PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Smith MI, Yatsunenko T, Manary MJ, Trehan I, Mkakosya R, Cheng J, et al. Gut microbiomes of Malawian twin pairs discordant for kwashiorkor. Science 2013;339:548–554PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 2013;499:97–101PubMedCrossRefGoogle Scholar
  25. 25.
    Shen J, Obin MS, Zhao L. The gut microbiota, obesity and insulin resistance. Mol Aspects Med 2013;34:39–58PubMedCrossRefGoogle Scholar
  26. 26.
    Morgan XC, Segata N, Huttenhower C. Biodiversity and functional genomics in the human microbiome. Trends Genet 2013;29:51–58PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Bukh J, Wantzin P, Krogsgaard K, Knudsen F, Purcell RH, Miller RH, Group CDHS. High prevalence of hepatitis C virus (HCV) RNA in dialysis patients: failure of commercially available antibody tests to identify a significant number of patients with HCV infection. J Infect Dis. 1993;168:1343–1348PubMedCrossRefGoogle Scholar
  28. 28.
    Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O’Huigin C, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 2009;461:798–801PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate ML, et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet 2009;41:1100–1104PubMedCrossRefGoogle Scholar
  30. 30.
    Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet 2009;41:1105–1109PubMedCrossRefGoogle Scholar
  31. 31.
    Rauch A, Kutalik Z, Descombes P, Cai T, Di Iulio J, Mueller T, et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology 2010;138:1338–1345 1345 e1331–1337PubMedCrossRefGoogle Scholar
  32. 32.
    Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med 2008;358:1160–1174PubMedCrossRefGoogle Scholar
  33. 33.
    Messersmith WA, Ahnen DJ. Targeting EGFR in colorectal cancer. N Engl J Med 2008;359:1834–1836PubMedCrossRefGoogle Scholar
  34. 34.
    Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008;359:1757–1765PubMedCrossRefGoogle Scholar
  35. 35.
    Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 2009;360:563–572PubMedCrossRefGoogle Scholar
  36. 36.
    Mayer RJ. Targeted therapy for advanced colorectal cancer–more is not always better. N Engl J Med 2009;360:623–625PubMedCrossRefGoogle Scholar
  37. 37.
    Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009;360:1408–1417PubMedCrossRefGoogle Scholar
  38. 38.
    Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 2008;26:5705–5712PubMedCrossRefGoogle Scholar
  39. 39.
    Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947–957PubMedCrossRefGoogle Scholar
  40. 40.
    Van Cutsem E, Labianca R, Bodoky G, Barone C, Aranda E, Nordlinger B, et al. Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J Clin Oncol 2009;27:3117–3125PubMedCrossRefGoogle Scholar
  41. 41.
    Van Cutsem E, Vervenne WL, Bennouna J, Humblet Y, Gill S, Van Laethem JL, et al. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol 2009;27:2231–2237PubMedCrossRefGoogle Scholar
  42. 42.
    Hidalgo M. Pancreatic cancer. N Engl J Med 2010;362:1605–1617PubMedCrossRefGoogle Scholar
  43. 43.
    Cunningham D, Atkin W, Lenz HJ, Lynch HT, Minsky B, Nordlinger B, et al. Colorectal cancer. Lancet 2010;375:1030–1047PubMedCrossRefGoogle Scholar
  44. 44.
    Wilmut I, Schnieke AE, McWhir J, Kind AJ, Campbell KH. Viable offspring derived from fetal and adult mammalian cells. Nature 1997;385:810–813PubMedCrossRefGoogle Scholar
  45. 45.
    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006;126:663–676PubMedCrossRefGoogle Scholar
  46. 46.
    Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 2007;318:1917–1920PubMedCrossRefGoogle Scholar
  47. 47.
    Tachibana M, Amato P, Sparman M, Gutierrez NM, Tippner-Hedges R, Ma H, et al. Human embryonic stem cells derived by somatic cell nuclear transfer. Cell 2013;153:1228–1238PubMedCrossRefGoogle Scholar
  48. 48.
    Fox IJ, Chowdhury JR, Kaufman SS, Goertzen TC, Chowdhury NR, Warkentin PI, et al. Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantation. N Engl J Med. 1998;338:1422–1426PubMedCrossRefGoogle Scholar
  49. 49.
    Muraca M, Gerunda G, Neri D, Vilei MT, Granato A, Feltracco P, et al. Hepatocyte transplantation as a treatment for glycogen storage disease type 1a. Lancet 2002;359:317–318PubMedCrossRefGoogle Scholar
  50. 50.
    Dhawan A, Mitry RR, Hughes RD, Lehec S, Terry C, Bansal S, et al. Hepatocyte transplantation for inherited factor VII deficiency. Transplantation 2004;78:1812–1814PubMedCrossRefGoogle Scholar
  51. 51.
    Strom SC, Chowdhury JR, Fox IJ. Hepatocyte transplantation for the treatment of human disease. Semin Liver Dis 1999;19:39–48PubMedCrossRefGoogle Scholar
  52. 52.
    Schneider A, Attaran M, Meier PN, Strassburg C, Manns MP, Ott M, et al. Hepatocyte transplantation in an acute liver failure due to mushroom poisoning. Transplantation 2006;82:1115–1116PubMedCrossRefGoogle Scholar
  53. 53.
    Roth DA, Tawa NE Jr, O’Brien JM, Treco DA, Selden RF. Nonviral transfer of the gene encoding coagulation factor VIII in patients with severe hemophilia A. N Engl J Med 2001;344:1735–1742PubMedCrossRefGoogle Scholar
  54. 54.
    Tauer CA. International policy failures: cloning and stem-cell research. Lancet 2004;364:209–214PubMedCrossRefGoogle Scholar
  55. 55.
    Donovan PJ, Gearhart J. The end of the beginning for pluripotent stem cells. Nature 2001;414:92–97PubMedCrossRefGoogle Scholar
  56. 56.
    Assady S, Maor G, Amit M, Itskovitz-Eldor J, Skorecki KL, Tzukerman M, et al. Insulin production by human embryonic stem cells. Diabetes. 2001;50:1691–1697PubMedCrossRefGoogle Scholar
  57. 57.
    Kehat I, Kenyagin-Karsenti D, Snir M, Segev H, Amit M, Gepstein A, et al. Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J Clin Invest 2001;108:407–414PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature 2001;414:105–111PubMedCrossRefGoogle Scholar
  59. 59.
    Spradling A, Drummond-Barbosa D, Kai T. Stem cells find their niche. Nature 2001;414:98–104PubMedCrossRefGoogle Scholar
  60. 60.
    Griffiths MJ, Bonnet D, Janes SM. Stem cells of the alveolar epithelium. Lancet 2005;366:249–260PubMedCrossRefGoogle Scholar
  61. 61.
    Bianco P, Robey PG. Stem cells in tissue engineering. Nature 2001;414:118–121PubMedCrossRefGoogle Scholar
  62. 62.
    Grompe M. The pathophysiology and treatment of hereditary tyrosinemia type 1. Semin Liver Dis 2001;21:563–571PubMedCrossRefGoogle Scholar
  63. 63.
    Nakagawa M, Koyanagi M, Tanabe K, Takahashi K, Ichisaka T, Aoi T, et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol 2008;26:101–106PubMedCrossRefGoogle Scholar
  64. 64.
    Hanna J, Wernig M, Markoulaki S, Sun CW, Meissner A, Cassady JP, et al. Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 2007;318:1920–1923PubMedCrossRefGoogle Scholar
  65. 65.
    Takebe T, Sekine K, Enomura M, Koike H, Kimura M, Ogaeri T, et al. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature 2013;499:481–484PubMedCrossRefGoogle Scholar
  66. 66.
    Abad M, Mosteiro L, Pantoja C, Canamero M, Rayon T, Ors I, et al. Reprogramming in vivo produces teratomas and iPS cells with totipotency features. Nature 2013;502:340–345PubMedCrossRefGoogle Scholar
  67. 67.
    Cohen DE, Melton D. Turning straw into gold: directing cell fate for regenerative medicine. Nat Rev Genet 2011;12:243–252PubMedCrossRefGoogle Scholar
  68. 68.
    Masip M, Veiga A, Izpisua Belmonte JC, Simon C. Reprogramming with defined factors: from induced pluripotency to induced transdifferentiation. Mol Hum Reprod 2010;16:856–868PubMedCrossRefGoogle Scholar
  69. 69.
    Xie H, Ye M, Feng R, Graf T. Stepwise reprogramming of B cells into macrophages. Cell 2004;117:663–676PubMedCrossRefGoogle Scholar
  70. 70.
    Cobaleda C, Jochum W, Busslinger M. Conversion of mature B cells into T cells by dedifferentiation to uncommitted progenitors. Nature 2007;449:473–477PubMedCrossRefGoogle Scholar
  71. 71.
    Efe JA, Hilcove S, Kim J, Zhou H, Ouyang K, Wang G, Chen J, et al. Conversion of mouse fibroblasts into cardiomyocytes using a direct reprogramming strategy. Nat Cell Biol 2011;13:215–222PubMedCrossRefGoogle Scholar
  72. 72.
    Qian L, Huang Y, Spencer CI, Foley A, Vedantham V, Liu L, et al. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature 2012;485:593–598PubMedCentralPubMedCrossRefGoogle Scholar
  73. 73.
    Song K, Nam YJ, Luo X, Qi X, Tan W, Huang GN, et al. Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature 2012;485:599–604PubMedCentralPubMedCrossRefGoogle Scholar
  74. 74.
    Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 2008;455:627–632PubMedCrossRefGoogle Scholar
  75. 75.
    Torper O, Pfisterer U, Wolf DA, Pereira M, Lau S, Jakobsson J, et al. Generation of induced neurons via direct conversion in vivo. Proc Natl Acad Sci USA 2013;110:7038–7043PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Ring KL, Tong LM, Balestra ME, Javier R, Andrews-Zwilling Y, Li G, et al. Direct reprogramming of mouse and human fibroblasts into multipotent neural stem cells with a single factor. Cell Stem Cell 2012;11:100–109PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Sekiya S, Suzuki A. Direct conversion of mouse fibroblasts to hepatocyte-like cells by defined factors. Nature 2011;475:390–393PubMedCrossRefGoogle Scholar
  78. 78.
    Ferreira LM, Mostajo-Radji MA. How induced pluripotent stem cells are redefining personalized medicine. Gene 2013;520:1–6PubMedCrossRefGoogle Scholar

Copyright information

© Asian Pacific Association for the Study of the Liver 2014

Authors and Affiliations

  1. 1.Department of Medicine IIUniversity Hospital FreiburgFreiburgGermany

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