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Human oocytes reprogram somatic cells to a pluripotent state

Abstract

The exchange of the oocyte’s genome with the genome of a somatic cell, followed by the derivation of pluripotent stem cells, could enable the generation of specific cells affected in degenerative human diseases. Such cells, carrying the patient’s genome, might be useful for cell replacement. Here we report that the development of human oocytes after genome exchange arrests at late cleavage stages in association with transcriptional abnormalities. In contrast, if the oocyte genome is not removed and the somatic cell genome is merely added, the resultant triploid cells develop to the blastocyst stage. Stem cell lines derived from these blastocysts differentiate into cell types of all three germ layers, and a pluripotent gene expression program is established on the genome derived from the somatic cell. This result demonstrates the feasibility of reprogramming human cells using oocytes and identifies removal of the oocyte genome as the primary cause of developmental failure after genome exchange.

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Figure 1: Developmental and transcriptional defects after genome exchange.
Figure 2: Development after somatic cell genome transfer with retention of the oocyte genome.
Figure 3: soPS cells are pluripotent.
Figure 4: Human oocytes reprogram a somatic cell to a pluripotent state.

Accession codes

Data deposits

Illumina array data have been deposited at GEO under accession number GSE28024.

References

  1. Wilmut, I., Schnieke, A. E., McWhir, J., Kind, A. J. & Campbell, K. H. Viable offspring derived from fetal and adult mammalian cells. Nature 385, 810–813 (1997)

    Article  CAS  ADS  Google Scholar 

  2. Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998)

    Article  CAS  ADS  Google Scholar 

  3. French, A. J. et al. Development of human cloned blastocysts following somatic cell nuclear transfer with adult fibroblasts. Stem Cells 26, 485–493 (2008)

    Article  CAS  Google Scholar 

  4. Hall, V. J. et al. Developmental competence of human in vitro aged oocytes as host cells for nuclear transfer. Hum. Reprod. 22, 52–62 (2007)

    Article  CAS  Google Scholar 

  5. Stojkovic, M. et al. Derivation of a human blastocyst after heterologous nuclear transfer to donated oocytes. Reprod. Biomed. Online 11, 226–231 (2005)

    Article  Google Scholar 

  6. Cibelli, J. et al. Somatic cell nuclear transfer in humans: pronuclear and early embryonic development. J. Regen. Med. 2, 25–31 (2001)

    Google Scholar 

  7. Kennedy, D. Editorial retraction. Science 311, 335 (2006)

    Article  CAS  Google Scholar 

  8. McElroy, S. L. et al. Developmental competence of immature and failed/abnormally fertilized human oocytes in nuclear transfer. Reprod. Biomed. Online 16, 684–693 (2008)

    Article  Google Scholar 

  9. Chung, Y. et al. Reprogramming of human somatic cells using human and animal oocytes. Cloning Stem Cells 11, 213–223 (2009)

    Article  CAS  Google Scholar 

  10. Heindryckx, B., De Sutter, P., Gerris, J., Dhont, M. & Van der Elst, J. Embryo development after successful somatic cell nuclear transfer to in vitro matured human germinal vesicle oocytes. Hum. Reprod. 22, 1982–1990 (2007)

    Article  CAS  Google Scholar 

  11. Egli, D., Chen, A. E., Melton, D. & Eggan, K. Impracticality of egg donor recruitment in the absence of compensation. Cell Stem Cell 10.1016/j.stem.2011.08.002 (in the press)

  12. 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 

  13. Chin, M. H. et al. Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures. Cell Stem Cell 5, 111–123 (2009)

    Article  CAS  Google Scholar 

  14. Ghosh, Z. et al. Persistent donor cell gene expression among human induced pluripotent stem cells contributes to differences with human embryonic stem cells. PLoS ONE 5, e8975 (2010)

    Article  ADS  Google Scholar 

  15. Doi, A. et al. Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nature Genet. 41, 1350–1353 (2009)

    Article  CAS  Google Scholar 

  16. Lister, R. et al. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 471, 68–73 (2011)

    Article  CAS  ADS  Google Scholar 

  17. Hu, B. Y. et al. Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency. Proc. Natl Acad. Sci. USA 107, 4335–4340 (2010)

    Article  CAS  ADS  Google Scholar 

  18. Gore, A. et al. Somatic coding mutations in human induced pluripotent stem cells. Nature 471, 63–67 (2011)

    Article  CAS  ADS  Google Scholar 

  19. Hussein, S. M. et al. Copy number variation and selection during reprogramming to pluripotency. Nature 471, 58–62 (2011)

    Article  CAS  ADS  Google Scholar 

  20. Mayshar, Y. et al. Identification and classification of chromosomal aberrations in human induced pluripotent stem cells. Cell Stem Cell 7, 521–531 (2010)

    Article  CAS  Google Scholar 

  21. Revazova, E. S. et al. Patient-specific stem cell lines derived from human parthenogenetic blastocysts. Cloning Stem Cells 9, 432–449 (2007)

    Article  CAS  Google Scholar 

  22. Egli, D., Chen, A. E., Melton, D. & Eggan, K. Reprogramming occurs within hours after mouse but not human nuclear transfer. Nature Commun. 10.1038/ncomms1503 (in the press)

  23. Klitzman, R. & Sauer, M. V. Payment of egg donors in stem cell research in the USA. Reprod. Biomed. Online 18, 603–608 (2009)

    Article  Google Scholar 

  24. Society for Assisted Reproductive Technology & the American Society for Reproductive Medicine . Assisted reproductive technology in the United States: 2001 results generated from the American Society for Reproductive Medicine/Society for Assisted Reproductive Technology registry. Fertil. Steril. 87, 1253–1266 (2007)

    Article  Google Scholar 

  25. The Ethics Committee of the American Society for Reproductive Medicine . Financial compensation of oocyte donors. Fertil. Steril. 88, 305–309 (2007)

    Article  Google Scholar 

  26. Daley, G. Q. et al. Ethics. The ISSCR guidelines for human embryonic stem cell research. Science 315, 603–604 (2007)

    Article  CAS  Google Scholar 

  27. Mitalipov, S. M. et al. Reprogramming following somatic cell nuclear transfer in primates is dependent upon nuclear remodeling. Hum. Reprod. 22, 2232–2242 (2007)

    Article  CAS  Google Scholar 

  28. Braude, P., Bolton, V. & Moore, S. Human gene expression first occurs between the four- and eight-cell stages of preimplantation development. Nature 332, 459–461 (1988)

    Article  CAS  ADS  Google Scholar 

  29. Draper, J. S. et al. Recurrent gain of chromosomes 17q and 12 in cultured human embryonic stem cells. Nature Biotechnol. 22, 53–54 (2004)

    Article  CAS  Google Scholar 

  30. Zhang, K. et al. Digital RNA allelotyping reveals tissue-specific and allele-specific gene expression in human. Nature Methods 6, 613–618 (2009)

    Article  CAS  Google Scholar 

  31. 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  CAS  ADS  Google Scholar 

  32. Kim, K. et al. Epigenetic memory in induced pluripotent stem cells. Nature 467, 285–290 (2010)

    Article  CAS  ADS  Google Scholar 

  33. Chen, A. E. et al. Optimal timing of inner cell mass isolation increases the efficiency of human embryonic stem cell derivation and allows generation of sibling cell lines. Cell Stem Cell 4, 103–106 (2009)

    Article  CAS  Google Scholar 

  34. Cowan, C. A. et al. Derivation of embryonic stem-cell lines from human blastocysts. N. Engl. J. Med. 350, 1353–1356 (2004)

    Article  CAS  Google Scholar 

  35. Dimos, J. T. et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321, 1218–1221 (2008)

    Article  CAS  ADS  Google Scholar 

  36. 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 

  37. Imamura, M. et al. Transcriptional repression and DNA hypermethylation of a small set of ES cell marker genes in male germline stem cells. BMC Dev. Biol. 6, 34 (2006)

    Article  Google Scholar 

  38. Pick, M. et al. Clone- and gene-specific aberrations of parental imprinting in human induced pluripotent stem cells. Stem Cells 27, 2686–2690 (2009)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank our research subjects for participating. We thank S. Solomon and K. Eggan for discussions and support, L. Bauer for help with blastocyst thawing, D. Kahler for cell sorting, M. Verbitsky and S. Kisselev for microarray hybridization, V. Miljkovic for Affymetrix SNP chip hybridization, C. LeDuc and Y. Ravussin for help with data analysis and mouse work, R. Maehr for DiPS H.1.5, C. Marshall and J. Safran for administrative support, S. Paull for cover art, Z. Hall and S. Chang for critical reading of the manuscript. This research was supported by a UCSD startup fund to K.Z., the New York Stem Cell Foundation primarily, and the Russell Berrie Foundation.

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Authors and Affiliations

Authors

Contributions

R.G. and M.V.S. wrote IRB and consent documents, M.V.S., K.C.S., K.O. and R.P. consented oocyte donors and retrieved oocytes, D.E. and S.N. designed and performed experiments with oocytes, D.E., H.-L.F., A.G., H.M., D.P. and K.Z. characterized stem cell lines, M.F., E.G. and M.V.S. performed skin biopsies, D.E. performed skin cell isolation, soPS and iPS derivation, S.D. performed NYSCF1 derivation, D.E. and R.L.L. wrote the paper with input from all authors. All work with human oocytes and stem cells was performed at the NYSCF laboratory.

Corresponding author

Correspondence to Dieter Egli.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-10 with Legends, Supplementary Karyotypes and Fingerprints, Supplementary Tables 1-7, a Supplementary Discussion and Supplementary References. (PDF 19560 kb)

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Noggle, S., Fung, HL., Gore, A. et al. Human oocytes reprogram somatic cells to a pluripotent state. Nature 478, 70–75 (2011). https://doi.org/10.1038/nature10397

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