Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Reprogramming of human somatic cells to pluripotency with defined factors

Abstract

Pluripotency pertains to the cells of early embryos that can generate all of the tissues in the organism. Embryonic stem cells are embryo-derived cell lines that retain pluripotency and represent invaluable tools for research into the mechanisms of tissue formation. Recently, murine fibroblasts have been reprogrammed directly to pluripotency by ectopic expression of four transcription factors (Oct4, Sox2, Klf4 and Myc) to yield induced pluripotent stem (iPS) cells. Using these same factors, we have derived iPS cells from fetal, neonatal and adult human primary cells, including dermal fibroblasts isolated from a skin biopsy of a healthy research subject. Human iPS cells resemble embryonic stem cells in morphology and gene expression and in the capacity to form teratomas in immune-deficient mice. These data demonstrate that defined factors can reprogramme human cells to pluripotency, and establish a method whereby patient-specific cells might be established in culture.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Differentiation of human embryonic fibroblasts from human embryonic stem cells (H1-OGN).
Figure 2: Multiple cultured human primary somatic cells yield iPS cells.
Figure 3: Gene expression in human iPS cells is similar to human ES cells.
Figure 4: iPS cells are demethylated at the OCT4 and NANOG promoters relative to their fibroblast parent lines.
Figure 5: Global gene expression analysis of iPS cells.
Figure 6: Xenografts of human iPS cells generate well-differentiated teratoma-like masses containing all three embryonic germ layers.

Similar content being viewed by others

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

The microarray data have been deposited in GEO and given the series accession number GSE9832.

References

  1. Wakayama, T. et al. Differentiation of embryonic stem cell lines generated from adult somatic cells by nuclear transfer. Science 292, 740–743 (2001)

    Article  ADS  CAS  Google Scholar 

  2. Cowan, C. A., Atienza, J., Melton, D. A. & Eggan, K. Nuclear reprogramming of somatic cells after fusion with human embryonic stem cells. Science 309, 1369–1373 (2005)

    Article  ADS  CAS  Google Scholar 

  3. Kanatsu-Shinohara, M. et al. Generation of pluripotent stem cells from neonatal mouse testis. Cell 119, 1001–1012 (2004)

    Article  CAS  Google Scholar 

  4. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006)

    Article  CAS  Google Scholar 

  5. Wernig, M. et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448, 318–324 (2007)

    Article  ADS  CAS  Google Scholar 

  6. Okita, K., Ichisaka, T. & Yamanaka, S. Generation of germline-competent induced pluripotent stem cells. Nature 448, 313–317 (2007)

    Article  ADS  CAS  Google Scholar 

  7. Maherali, N. et al. Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell 1, 55–70 (2007)

    Article  CAS  Google Scholar 

  8. Zwaka, T. P. & Thomson, J. A. Homologous recombination in human embryonic stem cells. Nature Biotechnol. 21, 319–321 (2003)

    Article  CAS  Google Scholar 

  9. Watanabe, K. et al. A ROCK inhibitor permits survival of dissociated human embryonic stem cells. Nature Biotechnol. 25, 681–686 (2007)

    Article  CAS  Google Scholar 

  10. Meissner, A., Wernig, M. & Jaenisch, R. Direct reprogramming of genetically unmodified fibroblasts into pluripotent stem cells. Nature Biotechnol. 25, 1177–1181 (2007)

    Article  CAS  Google Scholar 

  11. Blelloch, R., Venere, M., Yen, J. & Ramalho-Santos, M. Generation of induced pluripotent stem cells in the absence of drug selection. Cell Stem Cell 1, 245–247 (2007)

    Article  CAS  Google Scholar 

  12. Bodnar, A. G. et al. Extension of life-span by introduction of telomerase into normal human cells. Science 279, 349–352 (1998)

    Article  ADS  CAS  Google Scholar 

  13. Hahn, W. C. et al. Creation of human tumour cells with defined genetic elements. Nature 400, 464–468 (1999)

    Article  ADS  CAS  Google Scholar 

  14. Adewumi, O. et al. Characterization of human embryonic stem cell lines by the International Stem Cell Initiative. Nature Biotechnol. 25, 803–816 (2007)

    Article  CAS  Google Scholar 

  15. Tada, M., Takahama, Y., Abe, K., Nakatsuji, N. & Tada, T. Nuclear reprogramming of somatic cells by in vitro hybridization with ES cells. Curr. Biol. 11, 1553–1558 (2001)

    Article  CAS  Google Scholar 

  16. Lensch, M. W., Schlaeger, T. M., Zon, L. I. & Daley, G. Q. Teratoma formation assays with human embryonic stem cells: a rationale for one type of human-animal chimera. Cell Stem Cell 1, 253–258 (2007)

    Article  CAS  Google Scholar 

  17. Lensch, M. W. & Ince, T. A. The terminology of teratocarcinomas and teratomas. Nature Biotechnol. 25, 1211 (2007)

    Article  CAS  Google Scholar 

  18. Xu, C., Police, S., Rao, N. & Carpenter, M. K. Characterization and enrichment of cardiomyocytes derived from human embryonic stem cells. Circ. Res. 91, 501–508 (2002)

    Article  CAS  Google Scholar 

  19. Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007)

    Article  CAS  Google Scholar 

  20. Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science doi: 10.1126/science.1151526 (20 November 2007)

  21. Van Parijs, L. et al. Uncoupling IL-2 signals that regulate T cell proliferation, survival, and Fas-mediated activation-induced cell death. Immunity 11, 281–288 (1999)

    Article  CAS  Google Scholar 

  22. Eischen, C. M., Roussel, M. F., Korsmeyer, S. J. & Cleveland, J. L. Bax loss impairs Myc-induced apoptosis and circumvents the selection of p53 mutations during Myc-mediated lymphomagenesis. Mol. Cell. Biol. 21, 7653–7662 (2001)

    Article  CAS  Google Scholar 

  23. Deb-Rinker, P., Ly, D., Jezierski, A., Sikorska, M. & Walker, P. R. Sequential DNA methylation of the Nanog and Oct-4 upstream regions in human NT2 cells during neuronal differentiation. J. Biol. Chem. 280, 6257–6260 (2005)

    Article  CAS  Google Scholar 

  24. Freberg, C. T., Dahl, J. A., Timoskainen, S. & Collas, P. Epigenetic reprogramming of OCT4 and NANOG regulatory regions by embryonal carcinoma cell extract. Mol. Biol. Cell 18, 1543–1553 (2007)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research was funded by grants from the National Institutes of Health (NIH) and the NIH Director’s Pioneer Award of the NIH Roadmap for Medical Research, and made possible through the generosity of Joshua and Anita Bekenstein. G.Q.D. is a recipient of the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research.

Author Contributions I.-H.P. (project planning, experimental work, preparation of manuscript); R.Z., J.A.W., A.Y., H.H., P.H.L. (experimental work); T.A.I. (interpretation of teratoma pathology); M.W.L. (experimental work, preparation of manuscript); G.Q.D. (project planning, preparation of manuscript).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to George Q. Daley.

Supplementary information

Supplementary Information

The file contains Supplementary Figures S1-S9 with Legends and Supplementary Table 1. (PDF 4983 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Park, IH., Zhao, R., West, J. et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451, 141–146 (2008). https://doi.org/10.1038/nature06534

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature06534

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing