Skip to main content

Thank you for visiting 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.

Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes


Recent studies have suggested that bone marrow cells possess a broad differentiation potential, being able to form new liver cells, cardiomyocytes and neurons1,2. Several groups have attributed this apparent plasticity to ‘transdifferentiation’3,4,5. Others, however, have suggested that cell fusion could explain these results6,7,8,9. Using a simple method based on Cre/lox recombination to detect cell fusion events, we demonstrate that bone-marrow-derived cells (BMDCs) fuse spontaneously with neural progenitors in vitro. Furthermore, bone marrow transplantation demonstrates that BMDCs fuse in vivo with hepatocytes in liver, Purkinje neurons in the brain and cardiac muscle in the heart, resulting in the formation of multinucleated cells. No evidence of transdifferentiation without fusion was observed in these tissues. These observations provide the first in vivo evidence for cell fusion of BMDCs with neurons and cardiomyocytes, raising the possibility that cell fusion may contribute to the development or maintenance of these key cell types.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Method to detect cell fusion events.
Figure 2: Fusion of hepatocytes with BMDCs after bone marrow transplantation.
Figure 3: Purkinje cells fuse with BMDCs after bone marrow transplantation.
Figure 4: BMDCs fuse with cells in the heart.


  1. 1

    Morrison, S. J. Stem cell potential: can anything make anything? Curr. Biol. 11, R7–R9 (2001)

    CAS  Article  Google Scholar 

  2. 2

    Orkin, S. H. & Zon, L. I. Hematopoiesis and stem cells: plasticity versus developmental heterogeneity. Nature Immunol. 3, 323–328 (2002)

    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

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

    ADS  CAS  Article  Google Scholar 

  5. 5

    Priller, J. et al. Neogenesis of cerebellar Purkinje neurons from gene-marked bone marrow cells in vivo. J. Cell Biol. 155, 733–738 (2001)

    CAS  Article  Google Scholar 

  6. 6

    Terada, N. et al. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 416, 542–545 (2002)

    ADS  CAS  Article  Google Scholar 

  7. 7

    Ying, Q. L., Nichols, J., Evans, E. P. & Smith, A. G. Changing potency by spontaneous fusion. Nature 416, 545–548 (2002)

    ADS  CAS  Article  Google Scholar 

  8. 8

    Vassilopoulos, G., Wang, P. R. & Russell, D. W. Transplanted bone marrow regenerates liver by cell fusion. Nature 422, 901–904 (2003)

    ADS  CAS  Article  Google Scholar 

  9. 9

    Wang, X. et al. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 422, 897–901 (2003)

    ADS  CAS  Article  Google Scholar 

  10. 10

    Sauer, B. Inducible gene targeting in mice using the Cre/lox system. Methods 14, 381–392 (1998)

    CAS  Article  Google Scholar 

  11. 11

    Lewandoski, M., Meyers, E. N. & Martin, G. R. Analysis of Fgf8 gene function in vertebrate development. Cold Spring Harb. Symp. Quant. Biol. 62, 159–168 (1997)

    CAS  Article  Google Scholar 

  12. 12

    Mao, X., Fujiwara, Y. & Orkin, S. H. Improved reporter strain for monitoring Cre recombinase-mediated DNA excisions in mice. Proc. Natl Acad. Sci. USA 96, 5037–5042 (1999)

    ADS  CAS  Article  Google Scholar 

  13. 13

    Ianus, A., Holz, G. G., Theise, N. D. & Hussain, M. A. In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion. J. Clin. Invest. 111, 843–850 (2003)

    CAS  Article  Google Scholar 

  14. 14

    Weiss, S. et al. Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis. J. Neurosci. 16, 7599–7609 (1996)

    CAS  Article  Google Scholar 

  15. 15

    Palay, L. P. & Chan-Palay, V. Cerebellar Cortex 15–25 (Springer, Berlin, 1974)

    Book  Google Scholar 

  16. 16

    Weimann, J. M., Charlton, C. A., Brazelton, T. R., Hackman, R. C. & Blau, H. M. Contribution of transplanted bone marrow cells to Purkinje neurons in human adult brains. Proc. Natl Acad. Sci. USA 100, 2088–2093 (2003)

    ADS  CAS  Article  Google Scholar 

  17. 17

    Wagers, A. J., Sherwood, R. I., Christensen, J. L. & Weissman, I. L. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 297, 2256–2259 (2002)

    ADS  CAS  Article  Google Scholar 

  18. 18

    Ledbetter, J. A. & Herzenberg, L. A. Xenogeneic monoclonal antibodies to mouse lymphoid differentiation antigens. Immunol. Rev. 47, 63–90 (1979)

    CAS  Article  Google Scholar 

  19. 19

    van Ewijk, W., van Soest, P. L. & van den Engh, G. J. Fluorescence analysis and anatomic distribution of mouse T lymphocyte subsets defined by monoclonal antibodies to the antigens Thy-1, Lyt-1, Lyt-2, and T-200. J. Immunol. 127, 2594–2604 (1981)

    CAS  PubMed  Google Scholar 

  20. 20

    Ling, E. A. & Wong, W. C. The origin and nature of ramified and amoeboid microglia: a historical review and current concepts. Glia 7, 9–18 (1993)

    CAS  Article  Google Scholar 

  21. 21

    Gehrmann, J., Matsumoto, Y. & Kreutzberg, G. W. Microglia: intrinsic immuneffector cell of the brain. Brain Res. Brain Res. Rev. 20, 269–287 (1995)

    CAS  Article  Google Scholar 

  22. 22

    Arias, I. M., et al. The Liver Biology and Pathobiology (Lippincott Williams and Wilkins, Philadelphia, 2001)

    Google Scholar 

  23. 23

    Anderson, J. M. Multinucleated giant cells. Curr. Opin. Hematol. 7, 40–47 (2000)

    CAS  Article  Google Scholar 

  24. 24

    Piper, H. M. & Isenberg, I. Isolated Adult Cardiomyocytes (CRC, Boca Raton, 1989)

    Google Scholar 

  25. 25

    Lapham, L. W. Tetraploid DNA content of Purkinje neurons of human cerebellar cortex. Science 159, 310–312 (1968)

    ADS  CAS  Article  Google Scholar 

  26. 26

    Mares, V., Lodin, Z. & Sacha, J. A cytochemical and autoradiographic study of nuclear DNA in mouse Purkinje cells. Brain Res. 53, 273–289 (1973)

    CAS  Article  Google Scholar 

  27. 27

    Doetsch, F., Caille, I., Lim, D. A., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97, 703–716 (1999)

    CAS  Article  Google Scholar 

  28. 28

    Spector, D. L., Goldman, R. D. & Leinwand, L. A. Cells: a Laboratory Manual 4.1–4.7 (Cold Spring Harbor Laboratory Press, New York, 1998)

    Google Scholar 

  29. 29

    Hadjantonakis, A. K., Gertsenstein, M., Ikawa, M., Okabe, M. & Nagy, A. Generating green fluorescent mice by germline transmission of green fluorescent ES cells. Mech. Dev. 76, 79–90 (1998)

    CAS  Article  Google Scholar 

  30. 30

    Christensen, J. L. & Weissman, I. L. Flk-2 is a marker in hematopoietic stem cell differentiation: a simple method to isolate long-term stem cells. Proc. Natl Acad. Sci. USA 98, 14541–14546 (2001)

    ADS  CAS  Article  Google Scholar 

Download references


The authors thank G. Martin and P. Soriano for transgenic mouse lines, J. Maher at the UCSF Liver Centre for advice and assistance, and M. Kiel, O. Yilmaz and The University of Michigan Flow Cytometry Core for help with flow cytometry. R.P. thanks E. Schaller for technical help. M.A-D. thanks B. Rico, I. Cobos, T. Aragon and U. Borello for personal and scientific support. This work was supported by grants from NIH, the Sandler Foundation, the Spanish Ministry of Science and Technology (Ataxias Cerebelosa), and the Deutsche Forschungsgemeinschaft (DFG). R.P. was the recipient of a postdoctoral fellowship from the Spanish Ministry of Science and Technology.

Author information



Corresponding author

Correspondence to Arturo Alvarez-Buylla.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Alvarez-Dolado, M., Pardal, R., Garcia-Verdugo, J. et al. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 425, 968–973 (2003).

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.


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