Molecular Biotechnology

, Volume 52, Issue 2, pp 193–203

Human-Induced Pluripotent Stem Cells: In Quest of Clinical Applications

Review

Abstract

In the field of regenerative medicine, the development of induced pluripotent stem (iPS) cells may represent a potential strategy to overcome the limitations of human embryonic stem cells (ESCs). iPS cells have the potential to mimic human disease, since they carry the genome of the donor. Hypothetically, with iPS cell technology it is possible to screen patients for a genetic cause of disease (genetic mutation), develop cell lines, reprogram them back to iPS cells, finally differentiate them into one or more cell types that develop the disease. Although the creation of multiple lineages with iPS cells can seem limitless, a number of challenges need to be addressed in order to effectively use these cell lines for disease modeling. These include the low efficiency of iPS cell generation without genetic alterations, the possibility of tumor formation in vivo, the random integration of retroviral-based delivery vectors into the genome, and unregulated growth of the remaining cells that are partially reprogrammed and refractory to differentiation. The establishment of protein or RNA-based reprogramming strategies will help generate human iPS cells without permanent genetic alterations. Finally, direct reprogramming strategies can provide rapid production of models of human “diseases in a dish”, without first passing the cells through a pluripotent state, so avoiding the challenges of time-consumming and labor-intensive iPS cell line generation. This review will overview methods to develop iPS cells, current strategies for direct reprogramming, and main applications of iPS cells as human disease model, focusing on human cardiovascular diseases, with the aim to be a potential information resource for biomedical scientists and clinicians who exploit or intend to exploit iPS cell technology in a range of applications.

Keywords

Human-induced pluripotent stem cells Direct reprogramming Human disease models Gene regulation 

References

  1. 1.
    Abrams, D. J., Perkin, M. A., Skinner, J. R. (2010). Long QT syndrome. Praxis (Bern 1994) 99, 854–858.Google Scholar
  2. 2.
    Ambasudhan, R., Talantova, M., Coleman, R., Yuan, X., Zhu, S., Lipton, S. A., et al. (2011). Direct reprogramming of adult human fibroblasts to functional neurons under defined conditions. Cell Stem Cell, 9, 113–118.CrossRefGoogle Scholar
  3. 3.
    Axelrod, F. B. (2004). Familial dysautonomia. Muscle and Nerve, 29, 352–363.CrossRefGoogle Scholar
  4. 4.
    Bartel, D. P. (2004). MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell, 116, 281–297.CrossRefGoogle Scholar
  5. 5.
    Bentires-Alj, M., Kontaridis, M. I., & Neel, B. G. (2006). Stops along the RAS pathway in human genetic disease. Nature Medicine, 12, 283–285.CrossRefGoogle Scholar
  6. 6.
    Bibikova, M., Carroll, D., Segal, D. J., Trautman, J. K., Smith, J., Kim, Y. G., et al. (2001). Stimulation of homologous recombination through targeted cleavage by chimeric nucleases. Molecular and Cellular Biology, 21, 289–297.CrossRefGoogle Scholar
  7. 7.
    Bibikova, M., Golic, M., Golic, K. G., & Carroll, D. (2002). Targeted chromosomal cleavage and mutagenesis in Drosophila using zinc-finger nucleases. Genetics, 161, 1169–1175.Google Scholar
  8. 8.
    Brunet, E., Simsek, D., Tomishima, M., DeKelver, R., Choi, V. M., Gregory, P., et al. (2009). Chromosomal translocations induced at specified loci in human stem cells. Proceedings of the National Academy of Sciences of the United States of America, 106, 10620–10625.CrossRefGoogle Scholar
  9. 9.
    Caiazzo, M., Dell’anno, M. T., Dvoretskova, E., Lazarevic, D., Taverna, S., Leo, D., et al. (2011). Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature, 476, 224–227.CrossRefGoogle Scholar
  10. 10.
    Callaway, E. (2011). Cells snag top modelling job. Nature, 469, 279.CrossRefGoogle Scholar
  11. 11.
    Carey, B. W., Markoulaki, S., Hanna, J., Saha, K., Gao, Q., Mitalipova, M., et al. (2009). Reprogramming of murine and human somatic cells using a single polycistronic vector. Proceedings of the National Academy of Sciences of the United States of America, 106, 157–162.CrossRefGoogle Scholar
  12. 12.
    Carvajal-Vergara, X., Sevilla, A., D’Souza, S. L., Ang, Y. S., Schaniel, C., Lee, D. F., et al. (2010). Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome. Nature, 465, 808–812.CrossRefGoogle Scholar
  13. 13.
    Choi, J., Costa, M. L., Mermelstein, C. S., Chagas, C., Holtzer, S., & Holtzer, H. (1990). MyoD converts primary dermal fibroblasts, chondroblasts, smooth muscle, and retinal pigmented epithelial cells into striated mononucleated myoblasts and multinucleated myotubes. Proceedings of the National Academy of Sciences of the United States of America, 87, 7988–7992.CrossRefGoogle Scholar
  14. 14.
    Colman, A. (2008). Induced pluripotent stem cells and human disease. Cell Stem Cell, 3, 236–237.CrossRefGoogle Scholar
  15. 15.
    Coppin, B. D., & Temple, I. K. (1997). Multiple lentigines syndrome (LEOPARD syndrome or progressive cardiomyopathic lentiginosis). Journal of Medical Genetics, 34, 582–586.CrossRefGoogle Scholar
  16. 16.
    Curcic-Stojkovic, O., Nikolic, L., Obradovic, D., Krstic, A., & Radic, A. (1978). Noonan’s syndrome. (Male Turner’s syndrome, Turner-like syndrome). Med Pregl, 31, 299–303.Google Scholar
  17. 17.
    DeKelver, R. C., Choi, V. M., Moehle, E. A., Paschon, D. E., Hockemeyer, D., Meijsing, S. H., et al. (2010). Functional genomics, proteomics, and regulatory DNA analysis in isogenic settings using zinc finger nuclease-driven transgenesis into a safe harbor locus in the human genome. Genome Research, 20, 1133–1142.CrossRefGoogle Scholar
  18. 18.
    Dimos, J. T., Rodolfa, K. T., Niakan, K. K., Weisenthal, L. M., Mitsumoto, H., Chung, W., et al. (2008). Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science, 321, 1218–1221.CrossRefGoogle Scholar
  19. 19.
    Ebert, A. D., Yu, J., Rose, F. F, Jr, Mattis, V. B., Lorson, C. L., Thomson, J. A., et al. (2009). Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature, 457, 277–280.CrossRefGoogle Scholar
  20. 20.
    ***EMD Millipore. (2008). ENStem-A adherent human neural progenitors: A new source of primary human neural cells. Application Note.Google Scholar
  21. 21.
    Esteban, M. A., Wang, T., Qin, B., Yang, J., Qin, D., Cai, J., et al. (2010). Vitamin C enhances the generation of mouse and human induced pluripotent stem cells. Cell Stem Cell, 6, 71–79.CrossRefGoogle Scholar
  22. 22.
    Esteban, M. A., Xu, J., Yang, J., Peng, M., Qin, D., Li, W., et al. (2009). Generation of induced pluripotent stem cell lines from Tibetan miniature pig. Journal of Biological Chemistry, 284, 17634–17640.CrossRefGoogle Scholar
  23. 23.
    Hardouin, S. N., & Nagy, A. (2000). Mouse models for human disease. Clinical Genetics, 57, 237–244.CrossRefGoogle Scholar
  24. 24.
    Hedley, P. L., Jorgensen, P., Schlamowitz, S., Wangari, R., Moolman-Smook, J., Brink, P. A., et al. (2009). The genetic basis of long QT and short QT syndromes: A mutation update. Human Mutation, 30, 1486–1511.CrossRefGoogle Scholar
  25. 25.
    Hockemeyer, D., Soldner, F., Beard, C., Gao, Q., Mitalipova, M., DeKelver, R. C., et al. (2009). Efficient targeting of expressed and silent genes in human ESCs and iPSCs using zinc-finger nucleases. Nature Biotechnology, 27, 851–857.CrossRefGoogle Scholar
  26. 26.
    Huangfu, D., Maehr, R., Guo, W., Eijkelenboom, A., Snitow, M., Chen, A. E., et al. (2008). Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nature Biotechnology, 26, 795–797.CrossRefGoogle Scholar
  27. 27.
    Ichida, J. K., Blanchard, J., Lam, K., Son, E. Y., Chung, J. E., Egli, D., et al. (2009). A small-molecule inhibitor of tgf-Beta signaling replaces sox2 in reprogramming by inducing nanog. Cell Stem Cell, 5, 491–503.CrossRefGoogle Scholar
  28. 28.
    Ieda, M., Fu, J. D., Delgado-Olguin, P., Vedantham, V., Hayashi, Y., Bruneau, B. G., et al. (2010). Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell, 142, 375–386.CrossRefGoogle Scholar
  29. 29.
    Itzhaki, I., Maizels, L., Huber, I., Zwi-Dantsis, L., Caspi, O., Winterstern, A., et al. (2011). Modelling the long QT syndrome with induced pluripotent stem cells. Nature, 471, 225–229.CrossRefGoogle Scholar
  30. 30.
    Izumikawa, M., Minoda, R., Kawamoto, K., Abrashkin, K. A., Swiderski, D. L., Dolan, D. F., et al. (2005). Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals. Nature Medicine, 11, 271–276.CrossRefGoogle Scholar
  31. 31.
    Jackson, S. P., & Bartek, J. (2009). The DNA-damage response in human biology and disease. Nature, 461, 1071–1078.CrossRefGoogle Scholar
  32. 32.
    Kaji, K., Norrby, K., Paca, A., Mileikovsky, M., Mohseni, P., & Woltjen, K. (2009). Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature, 458, 771–775.CrossRefGoogle Scholar
  33. 33.
    Kim, J. B., Greber, B., Arauzo-Bravo, M. J., Meyer, J., Park, K. I., Zaehres, H., et al. (2009). Direct reprogramming of human neural stem cells by OCT4. Nature, 461, 649–653.CrossRefGoogle Scholar
  34. 34.
    Koch, P., Kokaia, Z., Lindvall, O., & Brustle, O. (2009). Emerging concepts in neural stem cell research: Autologous repair and cell-based disease modelling. Lancet Neurology, 8, 819–829.CrossRefGoogle Scholar
  35. 35.
    Krizhanovsky, V., & Lowe, S. W. (2009). Stem cells: The promises and perils of p53. Nature, 460, 1085–1086.CrossRefGoogle Scholar
  36. 36.
    Lee, G., Papapetrou, E. P., Kim, H., Chambers, S. M., Tomishima, M. J., Fasano, C. A., et al. (2009). Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature, 461, 402–406.CrossRefGoogle Scholar
  37. 37.
    Lombardo, A., Genovese, P., Beausejour, C. M., Colleoni, S., Lee, Y. L., Kim, K. A., et al. (2007). Gene editing in human stem cells using zinc finger nucleases and integrase-defective lentiviral vector delivery. Nature Biotechnology, 25, 1298–1306.CrossRefGoogle Scholar
  38. 38.
    Madonna, R., Shelat, H., De Caterina, R., & Geng, Y. (2011a). Aquaporin-1 is required for vascular development of human induced pluripotent stem cells following exposure to glucose-induced hyperosmolarity. Circulation AOS.701.01 (Abstract Oral Session).Google Scholar
  39. 39.
    ****Madonna, R., Shelat, H., De Caterina, R., and Geng, Y. J. (2011b). Vascularization in human induced pluripotent stem cells under hyperosmolarity induced by high glucose. J Am Coll Cardiol (abstr).Google Scholar
  40. 40.
    Madonna, R., Shelath, H., & Geng, Y. J. (2010). Aquaporin-associated vascular development of human induced pluripotent stem cells stimulated with high levels of glucose. Circulation, 122, A21260.Google Scholar
  41. 41.
    Miyoshi, N., Ishii, H., Nagano, H., Haraguchi, N., Dewi, D. L., Kano, Y., et al. (2011). Reprogramming of mouse and human cells to pluripotency using mature microRNAs. Cell Stem Cell, 8, 633–638.CrossRefGoogle Scholar
  42. 42.
    Moretti, A., Bellin, M., Welling, A., Jung, C. B., Lam, J. T., Bott-Flugel, L., et al. (2010). Patient-specific induced pluripotent stem-cell models for long-QT syndrome. New England Journal of Medicine, 363, 1397–1409.CrossRefGoogle Scholar
  43. 43.
    Nakajima, T., Furukawa, T., Tanaka, T., Katayama, Y., Nagai, R., Nakamura, Y., et al. (1998). Novel mechanism of HERG current suppression in LQT2: Shift in voltage dependence of HERG inactivation. Circulation Research, 83, 415–422.CrossRefGoogle Scholar
  44. 44.
    Nobelprize.org. (2007). The nobel prize in physiology or medicine 2007.Google Scholar
  45. 45.
    Okita, K., Hong, H., Takahashi, K., & Yamanaka, S. (2010). Generation of mouse-induced pluripotent stem cells with plasmid vectors. Nature Protocols, 5, 418–428.CrossRefGoogle Scholar
  46. 46.
    Pabo, C. O., Peisach, E., & Grant, R. A. (2001). Design and selection of novel Cys2His2 zinc finger proteins. Annual Review of Biochemistry, 70, 313–340.CrossRefGoogle Scholar
  47. 47.
    Pang, Z. P., Yang, N., Vierbuchen, T., Ostermeier, A., Fuentes, D. R., Yang, T. Q., et al. (2011). Induction of human neuronal cells by defined transcription factors. Nature, 476, 220–223.Google Scholar
  48. 48.
    Park, I. H., Arora, N., Huo, H., Maherali, N., Ahfeldt, T., Shimamura, A., et al. (2008). Disease-specific induced pluripotent stem cells. Cell, 134, 877–886.CrossRefGoogle Scholar
  49. 49.
    Pfisterer, U., Kirkeby, A., Torper, O., Wood, J., Nelander, J., Dufour, A., et al. (2011). Direct conversion of human fibroblasts to dopaminergic neurons. Proceedings of the National Academy of Sciences of the United States of America, 108, 10343–10348.CrossRefGoogle Scholar
  50. 50.
    Prior, T. W. (2007). Spinal muscular atrophy diagnostics. Journal of Child Neurology, 22, 952–956.CrossRefGoogle Scholar
  51. 51.
    Rao, M., & Condic, M. L. (2008). Alternative sources of pluripotent stem cells: Scientific solutions to an ethical dilemma. Stem Cells and Development, 17, 1–10.CrossRefGoogle Scholar
  52. 52.
    Raya, A., Rodriguez-Piza, I., Guenechea, G., Vassena, R., Navarro, S., Barrero, M. J., et al. (2009). Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature, 460, 53–59.CrossRefGoogle Scholar
  53. 53.
    Rosenthal, N., & Brown, S. (2007). The mouse ascending: perspectives for human-disease models. Nature Cell Biology, 9, 993–999.CrossRefGoogle Scholar
  54. 54.
    Sartipy, P., Bjorquist, P., Strehl, R., & Hyllner, J. (2007). The application of human embryonic stem cell technologies to drug discovery. Drug Discovery Today, 12, 688–699.CrossRefGoogle Scholar
  55. 55.
    Sinkkonen, L., Hugenschmidt, T., Berninger, P., Gaidatzis, D., Mohn, F., Artus-Revel, C. G., et al. (2008). MicroRNAs control de novo DNA methylation through regulation of transcriptional repressors in mouse embryonic stem cells. Nature Structural & Molecular Biology, 15, 259–267.CrossRefGoogle Scholar
  56. 56.
    Soldner, F., Hockemeyer, D., Beard, C., Gao, Q., Bell, G. W., Cook, E. G., et al. (2009). Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell, 136, 964–977.CrossRefGoogle Scholar
  57. 57.
    Somers, A., Jean, J. C., Sommer, C. A., Omari, A., Ford, C. C., Mills, J. A., et al. (2010). Generation of transgene-free lung disease-specific human induced pluripotent stem cells using a single excisable lentiviral stem cell cassette. Stem Cells, 28, 1728–1740.CrossRefGoogle Scholar
  58. 58.
    Stadtfeld, M., Nagaya, M., Utikal, J., Weir, G., & Hochedlinger, K. (2008). Induced pluripotent stem cells generated without viral integration. Science, 322, 945–949.CrossRefGoogle Scholar
  59. 59.
    Stewart, R., Yang, C., Anyfantis, G., Przyborski, S., Hole, N., Strachan, T., et al. (2008). Silencing of the expression of pluripotent driven-reporter genes stably transfected into human pluripotent cells. Regenerative Medicine, 3, 505–522.CrossRefGoogle Scholar
  60. 60.
    Sul, J. Y., Wu, C. W., Zeng, F., Jochems, J., Lee, M. T., Kim, T. K., et al. (2009). Transcriptome transfer produces a predictable cellular phenotype. Proceedings of the National Academy of Sciences of the United States of America, 106, 7624–7629.CrossRefGoogle Scholar
  61. 61.
    Szabo, E., Rampalli, S., Risueno, R. M., Schnerch, A., Mitchell, R., Fiebig-Comyn, A., et al. (2010). Direct conversion of human fibroblasts to multilineage blood progenitors. Nature, 468, 521–526.CrossRefGoogle Scholar
  62. 62.
    Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126, 663–676.CrossRefGoogle Scholar
  63. 63.
    Tanaka, T., Tohyama, S., Murata, M., Nomura, F., Kaneko, T., Chen, H., et al. (2009). In vitro pharmacologic testing using human induced pluripotent stem cell-derived cardiomyocytes. Biochemical and Biophysical Research Communications, 385, 497–502.CrossRefGoogle Scholar
  64. 64.
    Tay, Y., Zhang, J., Thomson, A. M., Lim, B., & Rigoutsos, I. (2008). MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature, 455, 1124–1128.CrossRefGoogle Scholar
  65. 65.
    Thomas, K. R., Folger, K. R., & Capecchi, M. R. (1986). High frequency targeting of genes to specific sites in the mammalian genome. Cell, 44, 419–428.CrossRefGoogle Scholar
  66. 66.
    Vierbuchen, T., Ostermeier, A., Pang, Z. P., Kokubu, Y., Sudhof, T. C., & Wernig, M. (2011). Direct conversion of fibroblasts to functional neurons by defined factors. Nature, 463, 1035–1041.CrossRefGoogle Scholar
  67. 67.
    Warren, L., Manos, P. D., Ahfeldt, T., Loh, Y. H., Li, H., Lau, F., et al. (2010). Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell, 7, 618–630.CrossRefGoogle Scholar
  68. 68.
    Wellner, U., Schubert, J., Burk, U. C., Schmalhofer, O., Zhu, F., Sonntag, A., et al. (2009). The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nature Cell Biology, 11, 1487–1495.CrossRefGoogle Scholar
  69. 69.
    Wernig, M., Zhao, J. P., Pruszak, J., Hedlund, E., Fu, D., Soldner, F., et al. (2008). Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson’s disease. Proceedings of the National Academy of Sciences of the United States of America, 105, 5856–5861.CrossRefGoogle Scholar
  70. 70.
    Woltjen, K., Michael, I. P., Mohseni, P., Desai, R., Mileikovsky, M., Hamalainen, R., et al. (2009). piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature, 458, 766–770.CrossRefGoogle Scholar
  71. 71.
    Xie, H., Ye, M., Feng, R., & Graf, T. (2004). Stepwise reprogramming of B cells into macrophages. Cell, 117, 663–676.CrossRefGoogle Scholar
  72. 72.
    Xu, N., Papagiannakopoulos, T., Pan, G., Thomson, J. A., & Kosik, K. S. (2009). MicroRNA-145 regulates OCT4, SOX2, and KLF4 and represses pluripotency in human embryonic stem cells. Cell, 137, 647–658.CrossRefGoogle Scholar
  73. 73.
    Ye, Z., Zhan, H., Mali, P., Dowey, S., Williams, D. M., Jang, Y. Y., et al. (2009). Human-induced pluripotent stem cells from blood cells of healthy donors and patients with acquired blood disorders. Blood, 114, 5473–5480.CrossRefGoogle Scholar
  74. 74.
    Yoshizaki, S., Nishi, M., Kondo, A., Kojima, Y., Yamamoto, N., & Ryo, A. (2010). Vaccination with human induced pluripotent stem cells creates an antigen-specific immune response against HIV-1 gp160. Frontiers in Microbiology, 2, 27.Google Scholar
  75. 75.
    Yu, J., Hu, K., Smuga-Otto, K., Tian, S., Stewart, R., Slukvin, I. I., et al. (2009). Human induced pluripotent stem cells free of vector and transgene sequences. Science, 324, 797–801.CrossRefGoogle Scholar
  76. 76.
    Yu, J., Vodyanik, M. A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J. L., Tian, S., et al. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science, 318, 1917–1920.CrossRefGoogle Scholar
  77. 77.
    Zhao, T., Zhang, Z. N., Rong, Z., & Xu, Y. (2011). Immunogenicity of induced pluripotent stem cells. Nature, 474, 212–215.CrossRefGoogle Scholar
  78. 78.
    Zou, J., Maeder, M. L., Mali, P., Pruett-Miller, S. M., Thibodeau-Beganny, S., Chou, B. K., et al. (2009). Gene targeting of a disease-related gene in human induced pluripotent stem and embryonic stem cells. Cell Stem Cell, 5, 97–110.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Institute of CardiologyG. d’Annunzio University-ChietiChietiItaly
  2. 2.Texas Heart Institute at St. Luke’s Episcopal HospitalThe University of Texas Health Science Center at HoustonHoustonUSA

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