Abstract
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 organs1–9. 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.
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References
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)
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)
Krause, D. S. et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 105, 369–377 (2001)
Lagasse, E. et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nature Med. 6, 1229–1234 (2000)
Clarke, D. L. et al. Generalized potential of adult neural stem cells. Science 288, 1660–1663 (2000)
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)
Ferrari, G. et al. Muscle regeneration by bone marrow-derived myogenic progenitors. Science 279, 1528–1530 (1998)
Orlic, D. et al. Bone marrow cells regenerate infarcted myocardium. Nature 410, 701–705 (2001)
Blau, H. M., Brazelton, T. R. & Weimann, J. M. The evolving concept of a stem cell: entity or function? Cell 105, 829–841 (2001)
Ephrussi, B. Hybridization of Somatic Cells (Princeton Univ. Press, Princeton, 1972)
Gardner, R. L. & Beddington, R. S. Multi-lineage ‘stem’ cells in the mammalian embryo. J. Cell Sci. 10 (Suppl.), 11–27 (1988)
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)
Galli, R. et al. Skeletal myogenic potential of human and mouse neural stem cells. Nature Neurosci. 3, 986–991 (2000)
Mountford, P. & Smith, A. G. Internal ribosome entry sites and dicistronic RNAs in mammalian transgenesis. Trends Genet. 11, 179–184 (1995)
Yeom, Y. I. et al. Germline regulatory element of Oct-4 specific for the totipotent cycle of embryonal cells. Development 122, 881–894 (1996)
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)
Mountford, P. et al. Dicistronic targeting constructs: reporters and modifiers of mammalian gene expression. Proc. Natl Acad. Sci. USA 91, 4303–4307 (1994)
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)
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)
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)
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)
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)
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)
Nagy, A. et al. Embryonic stem cells alone are able to support fetal development in the mouse. Development 110, 815–821 (1991)
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)
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)
Sorieul, S. & Ephrussi, B. Karyological demonstration of hybridization of mammalian cells in vitro. Nature 190, 653–654 (1961)
Smith, A. G. Culture and differentiation of embryonic stem cells. J. Tissue Culture Methods 13, 89–94 (1991)
Robertson, E. J. Teratocarcinoma and Embryo-derived Stem Cells: A Practical Approach (IRL, Oxford, 1987)
Acknowledgements
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.
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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.
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Ying, QL., Nichols, J., Evans, E. et al. Changing potency by spontaneous fusion. Nature 416, 545–548 (2002). https://doi.org/10.1038/nature729
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DOI: https://doi.org/10.1038/nature729
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