Skip to main content

Advertisement

SpringerLink
Log in

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

  • Review
  • Published:
Molecular Biotechnology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Abrams, D. J., Perkin, M. A., Skinner, J. R. (2010). Long QT syndrome. Praxis (Bern 1994) 99, 854–858.

  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.

    Article  CAS  Google Scholar 

  3. Axelrod, F. B. (2004). Familial dysautonomia. Muscle and Nerve, 29, 352–363.

    Article  Google Scholar 

  4. Bartel, D. P. (2004). MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell, 116, 281–297.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  10. Callaway, E. (2011). Cells snag top modelling job. Nature, 469, 279.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  14. Colman, A. (2008). Induced pluripotent stem cells and human disease. Cell Stem Cell, 3, 236–237.

    Article  CAS  Google Scholar 

  15. Coppin, B. D., & Temple, I. K. (1997). Multiple lentigines syndrome (LEOPARD syndrome or progressive cardiomyopathic lentiginosis). Journal of Medical Genetics, 34, 582–586.

    Article  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  20. ***EMD Millipore. (2008). ENStem-A adherent human neural progenitors: A new source of primary human neural cells. Application Note.

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  23. Hardouin, S. N., & Nagy, A. (2000). Mouse models for human disease. Clinical Genetics, 57, 237–244.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  31. Jackson, S. P., & Bartek, J. (2009). The DNA-damage response in human biology and disease. Nature, 461, 1071–1078.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  35. Krizhanovsky, V., & Lowe, S. W. (2009). Stem cells: The promises and perils of p53. Nature, 460, 1085–1086.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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).

  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).

  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. 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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  44. Nobelprize.org. (2007). The nobel prize in physiology or medicine 2007.

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  50. Prior, T. W. (2007). Spinal muscular atrophy diagnostics. Journal of Child Neurology, 22, 952–956.

    Article  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  53. Rosenthal, N., & Brown, S. (2007). The mouse ascending: perspectives for human-disease models. Nature Cell Biology, 9, 993–999.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  58. Stadtfeld, M., Nagaya, M., Utikal, J., Weir, G., & Hochedlinger, K. (2008). Induced pluripotent stem cells generated without viral integration. Science, 322, 945–949.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  71. Xie, H., Ye, M., Feng, R., & Graf, T. (2004). Stepwise reprogramming of B cells into macrophages. Cell, 117, 663–676.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. 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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  77. Zhao, T., Zhang, Z. N., Rong, Z., & Xu, Y. (2011). Immunogenicity of induced pluripotent stem cells. Nature, 474, 212–215.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

Download references

Conflict of interest

None declared.

Author information

Authors and Affiliations

  1. Institute of Cardiology, G. d’Annunzio University-Chieti, C/o Ospedale SS. Annunziata Via dei Vestini, 66013, Chieti, Italy

    Rosalinda Madonna

  2. Texas Heart Institute at St. Luke’s Episcopal Hospital, The University of Texas Health Science Center at Houston, Houston, TX, USA

    Rosalinda Madonna

Authors
  1. Rosalinda Madonna
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rosalinda Madonna.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Madonna, R. Human-Induced Pluripotent Stem Cells: In Quest of Clinical Applications. Mol Biotechnol 52, 193–203 (2012). https://doi.org/10.1007/s12033-012-9504-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12033-012-9504-0

Keywords

Search

Navigation