Changing potency by spontaneous fusion


Recent reports have suggested that mammalian stem cells residing in one tissue may have the capacity to produce differentiated cell types for other tissues and organs19. Here we define a mechanism by which progenitor cells of the central nervous system can give rise to non-neural derivatives. Cells taken from mouse brain were co-cultured with pluripotent embryonic stem cells. Following selection for a transgenic marker carried only by the brain cells, undifferentiated stem cells are recovered in which the brain cell genome has undergone epigenetic reprogramming. However, these cells also carry a transgenic marker and chromosomes derived from the embryonic stem cells. Therefore the altered phenotype does not arise by direct conversion of brain to embryonic stem cell but rather through spontaneous generation of hybrid cells. The tetraploid hybrids exhibit full pluripotent character, including multilineage contribution to chimaeras. We propose that transdetermination consequent to cell fusion10 could underlie many observations otherwise attributed to an intrinsic plasticity of tissue stem cells9.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Isolation and identification of descendants of ES and CNS cells.
Figure 2: Morphology and chromosomal constitution.
Figure 3: Pluripotency of hybrid cells.
Figure 4: Contribution of ZIN40/HT2 hybrid cells to chimaeras.


  1. 1

    Brazelton, T. R., Rossi, F. M., Keshet, G. I. & Blau, H. M. From marrow to brain: expression of neuronal phenotypes in adult mice. Science 290, 1775–1779 (2000)

    ADS  CAS  Article  Google Scholar 

  2. 2

    Mezey, E., Chandross, K. J., Harta, G., Maki, R. A. & McKercher, S. R. Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science 290, 1779–1782 (2000)

    ADS  CAS  Article  Google Scholar 

  3. 3

    Krause, D. S. et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 105, 369–377 (2001)

    CAS  Article  Google Scholar 

  4. 4

    Lagasse, E. et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nature Med. 6, 1229–1234 (2000)

    CAS  Article  Google Scholar 

  5. 5

    Clarke, D. L. et al. Generalized potential of adult neural stem cells. Science 288, 1660–1663 (2000)

    ADS  CAS  Article  Google Scholar 

  6. 6

    Bjornson, C. R., Rietze, R. L., Reynolds, B. A., Magli, M. C. & Vescovi, A. L. Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo. Science 283, 534–537 (1999)

    ADS  CAS  Article  Google Scholar 

  7. 7

    Ferrari, G. et al. Muscle regeneration by bone marrow-derived myogenic progenitors. Science 279, 1528–1530 (1998)

    ADS  CAS  Article  Google Scholar 

  8. 8

    Orlic, D. et al. Bone marrow cells regenerate infarcted myocardium. Nature 410, 701–705 (2001)

    ADS  CAS  Article  Google Scholar 

  9. 9

    Blau, H. M., Brazelton, T. R. & Weimann, J. M. The evolving concept of a stem cell: entity or function? Cell 105, 829–841 (2001)

    CAS  Article  Google Scholar 

  10. 10

    Ephrussi, B. Hybridization of Somatic Cells (Princeton Univ. Press, Princeton, 1972)

    Google Scholar 

  11. 11

    Gardner, R. L. & Beddington, R. S. Multi-lineage ‘stem’ cells in the mammalian embryo. J. Cell Sci. 10 (Suppl.), 11–27 (1988)

    CAS  Article  Google Scholar 

  12. 12

    Smith, A. in Stem Cell Biology (ed. Marshak, D. R.Gardner, R. L.Gottlieb, D.) 205–230 (Cold Spring Harbor Laboratory Press, New York, 2001)

    Google Scholar 

  13. 13

    Galli, R. et al. Skeletal myogenic potential of human and mouse neural stem cells. Nature Neurosci. 3, 986–991 (2000)

    CAS  Article  Google Scholar 

  14. 14

    Mountford, P. & Smith, A. G. Internal ribosome entry sites and dicistronic RNAs in mammalian transgenesis. Trends Genet. 11, 179–184 (1995)

    CAS  Article  Google Scholar 

  15. 15

    Yeom, Y. I. et al. Germline regulatory element of Oct-4 specific for the totipotent cycle of embryonal cells. Development 122, 881–894 (1996)

    CAS  Google Scholar 

  16. 16

    Lupton, S. D., Brunton, L. L., Kalberg, V. A. & Overell, R. W. Dominant positive and negative selection using a hygromycin phosphotransferase–thymidine kinase fusion gene. Mol. Cell. Biol. 11, 3374–3378 (1991)

    CAS  Article  Google Scholar 

  17. 17

    Mountford, P. et al. Dicistronic targeting constructs: reporters and modifiers of mammalian gene expression. Proc. Natl Acad. Sci. USA 91, 4303–4307 (1994)

    ADS  CAS  Article  Google Scholar 

  18. 18

    Niwa, H., Miyazaki, J. & Smith, A. G. Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nature Genet. 24, 372–376 (2000)

    CAS  Article  Google Scholar 

  19. 19

    Akeson, E. C. & Davisson, M. T. in Genetic Variants and Strains of the Laboratory Mouse (eds Lyon, M., Rastan, S. & Brown, S.) 1506–1509 (Oxford Univ. Press, Oxford, 1996)

    Google Scholar 

  20. 20

    Nichols, J. et al. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct-4. Cell 95, 379–391 (1998)

    CAS  Article  Google Scholar 

  21. 21

    Doetschman, T. C., Eistetter, H., Katz, M., Schmidt, W. & Kemler, R. The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium. J. Embryol. Exp. Morphol. 87, 27–45 (1985)

    CAS  PubMed  Google Scholar 

  22. 22

    Bain, G., Kitchens, D., Yao, M., Huettner, J. E. & Gottlieb, D. I. Embryonic stem cells express neuronal properties in vitro. Dev. Biol. 168, 342–357 (1995)

    CAS  Article  Google Scholar 

  23. 23

    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)

    CAS  Article  Google Scholar 

  24. 24

    Nagy, A. et al. Embryonic stem cells alone are able to support fetal development in the mouse. Development 110, 815–821 (1991)

    Google Scholar 

  25. 25

    Pratt, T., Sharp, L., Nichols, J., Price, D. J. & Mason, J. O. Embryonic stem cells and transgenic mice ubiquitously expressing a tau-tagged green fluorescent protein. Dev. Biol. 228, 19–28 (2000)

    CAS  Article  Google Scholar 

  26. 26

    Barski, G., Sorieul, S. & Cornefert, F. “Hybrid” type cells in combined cultures of two different mammalian cell strains. J. Natl Cancer Inst. 26, 1269–1291 (1961)

    CAS  PubMed  Google Scholar 

  27. 27

    Sorieul, S. & Ephrussi, B. Karyological demonstration of hybridization of mammalian cells in vitro. Nature 190, 653–654 (1961)

    ADS  Article  Google Scholar 

  28. 28

    Smith, A. G. Culture and differentiation of embryonic stem cells. J. Tissue Culture Methods 13, 89–94 (1991)

    Article  Google Scholar 

  29. 29

    Robertson, E. J. Teratocarcinoma and Embryo-derived Stem Cells: A Practical Approach (IRL, Oxford, 1987)

    Google Scholar 

Download references


H. Niwa and I. Chambers generated the HT2 ES cells and Marios Stavridis the 46C cells. We thank C. Graham for directing us to the original studies of Barski and Ephrussi and are grateful to C. Blackburn and A. Medvinksy for comments on the manuscript. This research was supported by the International Human Frontiers Science Program and by the Medical Research Council and Biotechnology and Biological Sciences Research Council of the UK.

Author information



Corresponding author

Correspondence to Austin G. Smith.

Ethics declarations

Competing interests

There is no patent filing or licensing agreement relating to the work

reported in this manuscript. A. Smith is a consultant to Stem Cell Sciences Ltd, a

biotechnology company specializing in embryonic stem cells. A. Smith also holds equity in

Stem Cell Sciences through a blind trust.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ying, Q., Nichols, J., Evans, E. et al. Changing potency by spontaneous fusion. Nature 416, 545–548 (2002).

Download citation

Further reading


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.


Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing