Therapeutic Possibilities of Induced Pluripotent Stem Cells

  • Harold Ayetey
Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)


A fundamental goal of human cell therapy is to regenerate ailing organs affected by congenital and acquired disease processes. Pluripotent stem cells such as embryonic stem (ES) cells can be differentiated into progenitor and fully differen­tiated cell types of all adult organs such as the brain, pancreas and the heart and therefore represent a promising source of cells for use in cell therapy for a variety of diseases. Importantly, the recent discovery that terminally differentiated somatic cells can be reprogrammed into induced pluripotent stem (iPS) cells with many of the properties of ES cells including the potential to generate diverse adult cell types bypasses important ethical concerns surrounding the derivation and use of human ES cells. Here, the therapeutic promise and limitations of these pluripotent cell types are discussed with a focus on iPS cells and their possible use in regenerative medicine, disease modeling and the development of pharmacological agents.


Pluripotency iPS cells Disease modeling Cell therapy Drug screening 



I thank Prof AG Smith for the opportunity to work in his distinguished laboratory and for critically reading this manuscript. I am grateful to Dr Andrew Grace for discussion on the application of iPS cells to cardiac electrophysiology, and am indebted to Dr Yasuhiro Takashima for experimental direction and technical help. I thank the Wellcome Trust for funding my Clinical Research Training Fellowship at the Cambridge Centre for Stem Cell Research and, finally, ESTOOLS for the opportunity to partake in useful collaborative work and educational activities across Europe.


  1. 1.
    Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS et al. Embryonic stem cell lines derived from human blastocysts. Science 1998; 282:1145–7. Erratum in: Science 1998; 282:1827.PubMedCrossRefGoogle Scholar
  2. 2.
    Smith AG. Embryo-derived stem cells: Of mice and men. Annu Rev Cell Dev Biol 2001; 17:435–62.PubMedCrossRefGoogle Scholar
  3. 3.
    Keller G. Embryonic stem cell differentiation: Emergence of a new era in biology and medicine. Genes Dev 2005; 19:1129–55.PubMedCrossRefGoogle Scholar
  4. 4.
    Jaenisch R. Human cloning, the science and ethics of therapeutic cloning. N Engl J Med 2004; 351:2787–91.PubMedCrossRefGoogle Scholar
  5. 5.
    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126:663–76. Epub 2006 Aug 10.PubMedCrossRefGoogle Scholar
  6. 6.
    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; 131:861–72.PubMedCrossRefGoogle Scholar
  7. 7.
    Yu J, Hu K, Smuga-Otto K, Tian S, Stewart R, Slukvin II et al. Human induced pluripotent stem cells free of vector and transgene sequences. Science 2009; 324:797–801.PubMedCrossRefGoogle Scholar
  8. 8.
    Maherali N, Sridharan R, Xie W, Utikal J, Eminli S, Arnold K et al. Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell 2007; 1:55–70.PubMedCrossRefGoogle Scholar
  9. 9.
    Meissner A, Wernig M, Jaenisch R. Direct reprogramming of genetically unmodified fibroblasts into pluripotent stem cells. Nat Biotechnol 2007; 25:1177–81.PubMedCrossRefGoogle Scholar
  10. 10.
    Okita K, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluripotent stem cells. Nature 2007; 448:313–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Wernig M, Meissner A, Foreman R, Brambrink T, Ku M, Hochedlinger K et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 2007; 448:318–24.PubMedCrossRefGoogle Scholar
  12. 12.
    Hockemeyer D, Soldner F, Beard C, Gao Q, Mitalipova M, DeKelver RC et al. Efficient targeting of expressed and silent genes in human ESCs and iPSCs using zinc-finger nucleases. Nat Biotechnol 2009; 27:851–7. Epub 2009 Aug 13.PubMedCrossRefGoogle Scholar
  13. 13.
    Sridharan R, Tchieu J, Mason MJ, Yachechko R, Kuoy E, Horvath S et al. Role of the murine reprogramming factors in the induction of pluripotency. Cell 2009; 136:364–77.PubMedCrossRefGoogle Scholar
  14. 14.
    Mikkelsen TS, Hanna J, Zhang X, Ku M, Wernig M, Schorderet P et al. Dissecting direct reprogramming through integrative genomic analysis. Nature 2008; 454:49–55.PubMedCrossRefGoogle Scholar
  15. 15.
    Amabile G, Meissner A. Induced pluripotent stem cells: Current progress and potential for regenerative medicine. Trends Mol Med 2009; 15:59–68. Epub 2009 Jan 21.PubMedCrossRefGoogle Scholar
  16. 16.
    Chin MH, Mason MJ, Xie W, Volinia S, Singer M, Peterson C et al. Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures. Cell Stem Cell 2009; 5:111–23.PubMedCrossRefGoogle Scholar
  17. 17.
    Marión RM, Strati K, Li H, Murga M, Blanco R, Ortega S et al. A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature 2009; 460:1149–53.PubMedCrossRefGoogle Scholar
  18. 18.
    Kawamura T, Suzuki J, Wang YV, Menendez S, Morera LB, Raya A et al. Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature 2009; 460:1140–4.PubMedCrossRefGoogle Scholar
  19. 19.
    Hong H, Takahashi K, Ichisaka T, Aoi T, Kanagawa O, Nakagawa M et al. Suppression of induced pluripotent stem cell generation by the p53–p21 pathway. Nature 2009; 460:1132–5.PubMedCrossRefGoogle Scholar
  20. 20.
    Utikal J, Polo JM, Stadtfeld M, Maherali N, Kulalert W, Walsh RM et al. Immortalization eliminates a roadblock during cellular reprogramming into iPS cells. Nature 2009; 460:1145–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Huangfu D, Osafune K, Maehr R, Guo W, Eijkelenboom A, Chen S et al. Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat Biotechnol 2008; 26:1269–75. Epub 2008 Oct 12.PubMedCrossRefGoogle Scholar
  22. 22.
    Lyssiotis CA, Foreman RK, Staerk J, Garcia M, Mathur D, Markoulaki S et al. Reprogramming of murine fibroblasts to induced pluripotent stem cells with chemical complementation of Klf4. Proc Natl Acad Sci USA 2009; 106:8912–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Bosnali M, Edenhofer F. Generation of transducible versions of transcription factors Oct4 and Sox2. Biol Chem 2008; 389:851–61.PubMedCrossRefGoogle Scholar
  24. 24.
    Zhou H, Wu S, Joo JY, Zhu S, Han DW, Lin T et al. Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 2009; 4:381–4. Epub 2009 Apr 23. Erratum in: Cell Stem Cell 2009 Jun 5; 4:581.PubMedCrossRefGoogle Scholar
  25. 25.
    Kaji K, Norrby K, Paca A, Mileikovsky M, Mohseni P, Woltjen K. Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 2009; 458:771–5.PubMedCrossRefGoogle Scholar
  26. 26.
    Woltjen K, Michael IP, Mohseni P, Desai R, Mileikovsky M, Hämäläinen R et al. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 2009; 458:766–70.PubMedCrossRefGoogle Scholar
  27. 27.
    Murry CE, Keller G. Differentiation of embryonic stem cells to clinically relevant populations: Lessons from embryonic development. Cell 2008; 132:661–80.PubMedCrossRefGoogle Scholar
  28. 28.
    Yang D, Zhang ZJ, Oldenburg M, Ayala M, Zhang SC. Human embryonic stem cell-derived dopaminergic neurons reverse functional deficit in parkinsonian rats. Stem Cells 2008; 26:55–63.PubMedCrossRefGoogle Scholar
  29. 29.
    Viczian AS, Solessio EC, Lyou Y, Zuber ME. Generation of functional eyes from pluripotent cells. PLoS Biol 2009; 7:e1000174.PubMedCrossRefGoogle Scholar
  30. 30.
    Rideout (III) WM, Hochedlinger K, Kyba M, Daley GQ, Jaenisch R. Correction of a genetic defect by nuclear transplantation and combined cell and gene therapy. Cell 2002; 109:17–27.CrossRefGoogle Scholar
  31. 31.
    Li M, Yu J, Li Y, Li D, Yan D, Qu Z et al. CXCR4 positive bone mesenchymal stem cells migrate to human endothelial cell stimulated by ox-LDL via SDF-1alpha/CXCR4 signaling axis. Exp Mol Pathol 2010; 88:250–5. Epub 2009 Dec 16.PubMedCrossRefGoogle Scholar
  32. 32.
    Wernig M, Zhao JP, Pruszak J, Hedlund E, Fu D, Soldner F et al. Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson’s disease. Proc Natl Acad Sci USA 2008; 105:5856–61.PubMedCrossRefGoogle Scholar
  33. 33.
    Xu D, Alipio Z, Fink LM, Adcock DM, Yang J, Ward DC et al. Phenotypic correction of murine hemophilia A using an iPS cell-based therapy. Proc Natl Acad Sci USA 2009; 106:808–13.PubMedCrossRefGoogle Scholar
  34. 34.
    Keirstead HS, Nistor G, Bernal G, Totoiu M, Cloutier F, Sharp K et al. Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci 2005; 25:4694–705.PubMedCrossRefGoogle Scholar
  35. 35.
    Sharp J, Keirstead HS. Stem cell-based cell replacement strategies for the central nervous system. Neurosci Lett 2009; 456:107–11.PubMedCrossRefGoogle Scholar
  36. 36.
    Schaefer A, Meyer GP, Fuchs M, Klein G, Kaplan M, Wollert KC et al. Impact of intracoronary bone marrow cell transfer on diastolic function in patients after acute myocardial infarction: Results from the BOOST trial. Eur Heart J 2006; 27:929–35.PubMedCrossRefGoogle Scholar
  37. 37.
    Abdel-Latif A, Bolli R, Tleyjeh IM, Montori VM, Perin EC, Hornung CA et al. Adult bone marrow-derived cells for cardiac repair: a systematic review and meta-analysis. Arch Intern Med 2007; 167:989–97.PubMedCrossRefGoogle Scholar
  38. 38.
    Schachinger V, Erbs S, Elsasser A. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med 2006; 355:1210–21.PubMedCrossRefGoogle Scholar
  39. 39.
    van der Laan A, Hirsch A, Nijveldt R, van der Vleuten PA, van der Giessen WJ, Doevendans PA et al. Bone marrow cell therapy after acute myocardial infarction: The HEBE trial in ­perspective, first results. Neth Heart J 2008; 16:436–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Laflamme MA, Chen KY, Naumova AV, Muskheli V, Fugate JA, Dupras SK et al. Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat Biotechnol 2007; 25:1015–24.PubMedCrossRefGoogle Scholar
  41. 41.
    van Laake LW, Passier R, Doevendans PA, Mummery CL. Human embryonic stem cell-derived cardiomyocytes and cardiac repair in rodents. Circ Res 2008; 102:1008–10.PubMedCrossRefGoogle Scholar
  42. 42.
    Yi BA, Wernet O, Chien KR. Pregenerative medicine: Developmental paradigms in the biology of cardiovascular regeneration. J Clin Invest 2010; 120:20–8. doi:  10.1172/JCI40820. Review.PubMedCrossRefGoogle Scholar
  43. 43.
    Moretti A, Bellin M, Jung CB, Thies TM, Takashima Y, Bernshausen A et al. Mouse and human induced pluripotent stem cells as a source for multipotent Isl1+ cardiovascular progenitors. FASEB J 2010 Mar; 24:700–11. Epub 2009 Oct 22.PubMedCrossRefGoogle Scholar
  44. 44.
    Bu L, Jiang X, Martin-Puig S, Caron L, Zhu S, Shao Y et al. Human ISL1 heart progenitors generate diverse multipotent cardiovascular cell lineages. Nature 2009; 460:113–7.PubMedCrossRefGoogle Scholar
  45. 45.
    Patterson CC, Dahlquist GG, Gyurus E, Green A, Soltesz G. Incidence trends for childhood type 1 diabetes in Europe during 1989–2003 and predicted new cases 2005–20: A multicenter prospective registration study. Lancet 2009; 373:2027–33.PubMedCrossRefGoogle Scholar
  46. 46.
    Scharp DW, Lacy PE, Santiago JV, McCullough CS, Weide LG, Boyle PJ et al. Results of our first nine intraportal islet allografts in type 1, insulin dependent diabetic patients. Transplantation 1991; 51:76–85.PubMedCrossRefGoogle Scholar
  47. 47.
    Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000; 343:230–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Alejandro R, Barton FB, Hering BJ, Wease S. Update from the Collaborative Islet Transplant Registry. Transplantation 2008; 86:1783–8.PubMedCrossRefGoogle Scholar
  49. 49.
    D’Amour KA, Bang AG, Eliazer S, Kelly OG, Agulnick AD, Smart NG et al. Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat Biotechnol 2006; 24:1392–401.PubMedCrossRefGoogle Scholar
  50. 50.
    Kroon E, Martinson LA, Kadoya K, Bang AG, Kelly OG, Eliazer S et al. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol 2008; 26:443–52.PubMedCrossRefGoogle Scholar
  51. 51.
    Maehr R, Chen S, Snitow M, Ludwig T, Yagasaki L, Goland R et al. Generation of pluripotent stem cells from patients with type 1 diabetes. Proc Natl Acad Sci USA 2009; 106:15768–73.PubMedCrossRefGoogle Scholar
  52. 52.
    Van Hoof D, D’Amour KA, German MS. Derivation of insulin-producing cells from human embryonic stem cells. Stem Cell Res 2009; 3:73–87. Epub 2009 Aug 26.PubMedCrossRefGoogle Scholar
  53. 53.
    Buchholz DE, Hikita ST, Rowland TJ, Friedrich AM, Hinman CR, Johnson LV et al. Derivation of functional retinal pigmented epithelium from induced pluripotent stem cells. Stem Cells 2009; 27:2427–34.PubMedCrossRefGoogle Scholar
  54. 54.
    Vugler A, Carr AJ, Lawrence J, Chen LL, Burrell K, Wright A et al. Elucidating the phenomenon of HESC-derived RPE: anatomy of cell genesis, expansion and retinal transplantation. Exp Neurol 2008; 214:347–61. Epub 2008 Sep 27.PubMedCrossRefGoogle Scholar
  55. 55.
    Qiao H, Lucas K, Stein-Streilein J. Retinal laser burn disrupts immune privilege in the eye. Am J Pathol 2009; 174:414–22.PubMedCrossRefGoogle Scholar
  56. 56.
    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; 318:1920–3.PubMedCrossRefGoogle Scholar
  57. 57.
    Wang Y, Jiang Y, Liu S, Sun X, Gao S. Generation of induced pluripotent stem cells from human beta-thalassemia fibroblast cells. Cell Res 2009; 19:1120–3. Epub 2009 Aug 18.PubMedCrossRefGoogle Scholar
  58. 58.
    Sothern RB, Gruber SA. Further commentary: physiological parameters in laboratory animals and humans. Pharm Res 1994; 11:349–50.PubMedCrossRefGoogle Scholar
  59. 59.
    Park I-H, Aurora N, Huo H, Ahfeldt T, Maherali N, Shimamura A, Lensch W, Cowan C, Hochedlinger C and Daley G. Q. Disease-specific induced pluripotent stem cells. Cell 2008; 134:1–10.CrossRefGoogle Scholar
  60. 60.
    Ebert AD, Yu J, Rose FF Jr, Mattis VB, Lorson CL, Thomson JA et al. Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 2009; 457:277–80. Epub 2008 Dec 21.PubMedCrossRefGoogle Scholar
  61. 61.
    Di Giorgio FP, Boulting GL, Bobrowicz S, Eggan KC. Human embryonic stem cell-derived motor neurons are sensitive to the toxic effect of glial cells carrying an ALS-causing mutation. Cell Stem Cell 2008; 3:637–48. PMID:19041780.PubMedCrossRefGoogle Scholar
  62. 62.
    Di Giorgio FP, Carrasco MA, Siao MC, Maniatis T, Eggan K. Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nat Neurosci 2007; 10:608–14. Epub 2007 Apr 15.PubMedCrossRefGoogle Scholar
  63. 63.
    Marchetto MC, Muotri AR, Mu Y, Smith AM, Cezar GG, Gage FH. Non-cell-autonomous effect of human SOD1 G37R astrocytes on motor neurons derived from human embryonic stem cells. Cell Stem Cell 2008; 3:649–57.PubMedCrossRefGoogle Scholar
  64. 64.
    Lee G, Papapetrou EP, Kim H, Chambers SM, Tomishima MJ, Fasano CA et al. Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature 2009; 461:402–6. Epub 2009 Aug 19.PubMedCrossRefGoogle Scholar
  65. 65.
    Raya I, Rodríguez-Pizà G, Guenechea R, Vassena S, Navarro MJ, Barrero A et al. Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature 2009; 460:53–9.PubMedCrossRefGoogle Scholar
  66. 66.
    Ye Z, Zhan H, Mali P, Dowey S, Williams DM, Jang YY et al. Human-induced pluripotent stem cells from blood cells of healthy donors and patients with acquired blood disorders. Blood 2009; 114:5473–80. Epub 2009 Oct 1.PubMedCrossRefGoogle Scholar
  67. 67.
    Schwartz PJ, Crotti L. Long QT and short QT syndrome. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside. 5th ed. Philadelphia, PA: Elsevier/Saunders; 2009:731–44.Google Scholar
  68. 68.
    Crotti L, Lundquist AL, Insolia R, Pedrazzini M, Ferrandi C, De Ferrari GM et al. KCNH2-K897T is a genetic modifier of latent congenital long-QT syndrome. Circulation 2005; 112:1251–8.PubMedCrossRefGoogle Scholar
  69. 69.
    Schwartz PJ, Priori SG, Napolitano C. How really rare are rare diseases? The intriguing case of independent compound mutations in the long QT syndrome. J Cardiovasc Electrophysiol 2003; 14:1120–1.PubMedCrossRefGoogle Scholar
  70. 70.
    Westenskow P, Splawski I, Timothy KW, Keating MT, Sanguinetti MC. Compound mutations: A common cause of severe long-QT syndrome. Circulation 2004; 109:1834–41.PubMedCrossRefGoogle Scholar
  71. 71.
    London B. Cardiac arrhythmias: From (transgenic) mice to men. J Cardiovasc Electrophysiol 2001; 12:1089–91.PubMedCrossRefGoogle Scholar
  72. 72.
    Nerbonne JM, Nichols CG, Schwarz TL, Escande D. Genetic manipulation of cardiac K  +  channel function in mice: What have we learned, and where do we go from here? Circ Res 2001; 89:944–56.PubMedCrossRefGoogle Scholar
  73. 73.
    Crotti L, Monti MC, Insolia R, Peljto A, Goosen A, Brink PA et al. NOS1AP is a genetic modifier of the Long QT syndrome. Circulation 2009; 120:1657–63.PubMedCrossRefGoogle Scholar
  74. 74.
    Cavero I, Crumb W. ICH S7B draft guideline on the non-clinical strategy for testing delayed cardiac repolarisation risk of drugs: A critical analysis. Expert Opin Drug Saf 2005; 4:509–30. Review.PubMedCrossRefGoogle Scholar
  75. 75.
    Cao F, Lin S, Xie X, Ray P, Patel M, Zhang X et al. In vivo visualization of embryonic stem cell survival, proliferation, and migration after cardiac delivery. Circulation 2006; 113:1005–14.PubMedCrossRefGoogle Scholar
  76. 76.
    Li Z, Suzuki Y, Huang M, Cao F, Xie X, Connolly AJ et al. Comparison of reporter gene and iron particle labeling for tracking fate of human embryonic stem cells and differentiated endothelial cells in living subjects. Stem Cells 2008; 26:864–73.PubMedCrossRefGoogle Scholar
  77. 77.
    Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Südhof TC, Wernig M. Direct conversion of fibroblasts to functional neurons by defined factors. Nature 2010; 463:1035–41. Epub 2010 Jan 27.PubMedCrossRefGoogle Scholar
  78. 78.
    Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 2008; 455:627–32.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Harold Ayetey
    • 1
    • 2
    • 3
  1. 1.Department of MedicineUniversity of Cambridge, Wellcome Trust Centre for Stem Cell ResearchCambridgeUK
  2. 2.Cambridge University Hospitals NHS Foundation TrustCambridge
  3. 3.Clare CollegeCambridge

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