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.

  • Letter
  • Published:

Extensive fusion of haematopoietic cells with Purkinje neurons in response to chronic inflammation

Abstract

Transplanted bone marrow-derived cells (BMDCs) have been reported to fuse with cells of diverse tissues1,2,3,4,5,6,7,8,9,10,11,12,13, but the extremely low frequency of fusion has led to the view that such events are biologically insignificant. Nonetheless, in mice with a lethal recessive liver disease (tyrosinaemia), transplantation of wild-type BMDCs restored liver function by cell fusion and prevented death3,9, indicating that cell fusion can have beneficial effects. Here we report that chronic inflammation resulting from severe dermatitis or autoimmune encephalitis leads to robust fusion of BMDCs with Purkinje neurons and formation of hundreds of binucleate heterokaryons per cerebellum, a 10–100-fold higher frequency than previously reported8,10,11,14. Single haematopoietic stem-cell transplants showed that the fusogenic cell is from the haematopoietic lineage and parabiosis experiments revealed that fusion can occur without irradiation. Transplantation of rat bone marrow into mice led to activation of dormant rat Purkinje neuron-specific genes in BMDC nuclei after fusion with mouse Purkinje neurons, consistent with nuclear reprogramming. The precise neurological role of these heterokaryons awaits elucidation, but their frequency in brain after inflammation is clearly much higher than previously appreciated.

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: Progeny of a single HSC can form heterokaryons with Purkinje neurons and the formation of cerebellar heterokaryons is independent of variables associated with bone marrow transplantation.
Figure 2: Idiopathic ulcerative dermatitis modulates cerebellar heterokaryons.
Figure 3: Heterokaryon formation is increased by inflammation induced by either idiopathic ulcerative dermatitis or experimental autoimmune encephalitis (EAE), but not by LPS induced inflammation.
Figure 4: Rat neural-gene expression in heterokaryons of mice transplanted with rat bone marrow.

Similar content being viewed by others

References

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

    Article  CAS  Google Scholar 

  2. Bittner, R. E. et al. Recruitment of bone-marrow-derived cells by skeletal and cardiac muscle in adult dystrophic mdx mice. Anat. Embryol. 199, 391–396 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. LaBarge, M. A. & Blau, H. M. Biological progression from adult bone marrow to mononucleate muscle stem cell to multinucleate muscle fiber in response to injury. Cell 111, 589–601. (2002).

    Article  CAS  Google Scholar 

  5. Fukada, S. et al. Muscle regeneration by reconstitution with bone marrow or fetal liver cells from green fluorescent protein-gene transgenic mice. J. Cell Sci. 115, 1285–1293 (2002).

    CAS  PubMed  Google Scholar 

  6. Camargo, F. D., Green, R., Capetenaki, Y., Jackson, K. A. & Goodell, M. A. Single hematopoietic stem cells generate skeletal muscle through myeloid intermediates. Nature Med. 9, 1520–1527 (2003).

    Article  CAS  Google Scholar 

  7. Corbel, S. Y. et al. Contribution of hematopoietic stem cells to skeletal muscle. Nature Med. 9, 1528–1532 (2003).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

  10. 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).

    Article  CAS  Google Scholar 

  11. Weimann, J. M., Johansson, C. B., Trejo, A. & Blau, H. M. Stable reprogrammed heterokaryons form spontaneously in Purkinje neurons after bone marrow transplant. Nature Cell Biol. 5, 959–966 (2003).

    Article  CAS  Google Scholar 

  12. Rizvi, A. Z. et al. Bone marrow-derived cells fuse with normal and transformed intestinal stem cells. Proc. Natl Acad. Sci. USA 103, 6321–6325 (2006).

    Article  CAS  Google Scholar 

  13. Herzog, E. L. et al. Lung-specific nuclear reprogramming is accompanied by heterokaryon formation and Y chromosome loss following bone marrow transplantation and secondary inflammation. FASEB J. 21, 2592–2601 (2007).

    Article  CAS  Google Scholar 

  14. Massengale, M., Wagers, A. J., Vogel, H. & Weissman, I. L. Hematopoietic cells maintain hematopoietic fates upon entering the brain. J. Exp. Med. 201, 1579–1589 (2005).

    Article  CAS  Google Scholar 

  15. Miyamoto, T. The dendritic cell-specific transmembrane protein DC-STAMP is essential for osteoclast fusion and osteoclast bone-resorbing activity. Mod. Rheumatol. Jpn Rheumat. Assoc. 16, 341–342 (2006).

    Article  CAS  Google Scholar 

  16. Huppertz, B., Bartz, C. & Kokozidou, M. Trophoblast fusion: fusogenic proteins, syncytins and ADAMs, and other prerequisites for syncytial fusion. Micron 37, 509–517 (2006).

    Article  CAS  Google Scholar 

  17. Pajcini, K. V., Pomerantz, J. H., Alkan, O., Doyonnas, R. & Blau, H. M. Myoblasts and macrophages share molecular components that contribute to cell-cell fusion. J. Cell Biol. 180, 1005–1019 (2008).

    Article  CAS  Google Scholar 

  18. Sacco, A. et al. IGF-I increases bone marrow contribution to adult skeletal muscle and enhances the fusion of myelomonocytic precursors. J. Cell Biol. 171, 483–492 (2005).

    Article  CAS  Google Scholar 

  19. 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).

    Article  CAS  Google Scholar 

  20. Pachter, J. S., de Vries, H. E. & Fabry, Z. The blood-brain barrier and its role in immune privilege in the central nervous system. J. Neuropathol. Exp. Neurol. 62, 593–604 (2003).

    Article  CAS  Google Scholar 

  21. Yuan, H. et al. Effects of fractionated radiation on the brain vasculature in a murine model: blood-brain barrier permeability, astrocyte proliferation, and ultrastructural changes. Int. J. Rad. Oncol. Biol. Phys. 66, 860–866 (2006).

    Article  Google Scholar 

  22. Wright, D. E., Wagers, A. J., Gulati, A. P., Johnson, F. L. & Weissman, I. L. Physiological migration of hematopoietic stem and progenitor cells. Science 294, 1933–1936 (2001).

    Article  CAS  Google Scholar 

  23. Kastenmayer, R. J., Fain, M. A. & Perdue, K. A. A retrospective study of idiopathic ulcerative dermatitis in mice with a C57BL/6 background. J. Am. Assoc. Lab. Anim. Sci. 45, 8–12 (2006).

    CAS  PubMed  Google Scholar 

  24. Ajami, B., Bennett, J. L., Krieger, C., Tetzlaff, W. & Rossi, F. M. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nature Neurosci. 10, 1538–1543 (2007).

    Article  CAS  Google Scholar 

  25. Fendrick, S. E., Xue, Q. S. & Streit, W. J. Formation of multinucleated giant cells and microglial degeneration in rats expressing a mutant Cu/Zn superoxide dismutase gene. J. Neuroinflam. 4, 9 (2007).

    Article  Google Scholar 

  26. Rock, R. B. et al. Role of microglia in central nervous system infections. Clin. Microbiol. Rev. 17, 942–964, Table of contents (2004).

    Article  CAS  Google Scholar 

  27. Doyonnas, R., LaBarge, M. A., Sacco, A., Charlton, C. & Blau, H. M. Hematopoietic contribution to skeletal muscle regeneration by myelomonocytic precursors. Proc. Natl Acad. Sci. USA 101, 13507–13512 (2004).

    Article  CAS  Google Scholar 

  28. Kornek, B. et al. Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am. J. Pathol. 157, 267–276. (2000).

    Article  CAS  Google Scholar 

  29. Linker, R. A. et al. EAE in beta-2 microglobulin-deficient mice: axonal damage is not dependent on MHC-I restricted immune responses. Neurobiol. Dis. 19, 218–228 (2005).

    Article  CAS  Google Scholar 

  30. Gold, R., Linington, C. & Lassmann, H. Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 129, 1953–1971 (2006).

    Article  Google Scholar 

  31. Ousman, S. S. et al. Protective and therapeutic role for αB-crystallin in autoimmune demyelination. Nature 448, 474–479 (2007).

    Article  CAS  Google Scholar 

  32. Ildstad, S. T. et al. Cross-species bone marrow transplantation: evidence for tolerance induction, stem cell engraftment, and maturation of T lymphocytes in a xenogeneic stromal environment (rat----mouse). J. Exp. Med. 174, 467–478 (1991).

    Article  CAS  Google Scholar 

  33. Ikarashi, K. et al. Bone marrow cells contribute to regeneration of damaged glomerular endothelial cells. Kidney Int. 67, 1925–1933 (2005).

    Article  CAS  Google Scholar 

  34. Sacco, T., De Luca, A. & Tempia, F. Properties and expression of Kv3 channels in cerebellar Purkinje cells. Mol. Cell. Neurosci. 33, 170–179 (2006).

    Article  CAS  Google Scholar 

  35. Hall, K. U. et al. Phosphorylation-dependent inhibition of protein phosphatase-1 by G-substrate. A Purkinje cell substrate of the cyclic GMP-dependent protein kinase. J. Biol. Chem. 274, 3485–3495 (1999).

    Article  CAS  Google Scholar 

  36. Stewart, F. M. et al. Host marrow stem cell potential and engraftability at varying times after low-dose whole-body irradiation. Blood 98, 1246–1251 (2001).

    Article  CAS  Google Scholar 

  37. Johansson, C. B. et al. Identification of a neural stem cell in the adult mammalian central nervous system. Cell 96, 25–34 (1999).

    Article  CAS  Google Scholar 

  38. Bunster, E. & Meyer, R. K. An improved method of parabiosis. Anat. Rec. 57, 339–343 (1933).

    Article  Google Scholar 

  39. Palermo, A. T., Labarge, M. A., Doyonnas, R., Pomerantz, J. & Blau, H. M. Bone marrow contribution to skeletal muscle: a physiological response to stress. Dev. Biol. 279, 336–344 (2005).

    Article  CAS  Google Scholar 

  40. Youssef, S. et al. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 420, 78–84 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to the members of the Blau laboratory for helpful discussions; Mark LaBarge, Timothy Brazelton, Christine Dieterich, Tomas Olsson, Jonas Frisen and Lou Brundin for valuable discussions and critical reading of the manuscript; Corrine Davis for expert assistance with the evaluation of skin pathology; Peggy Kraft and Angelica Trejo for expert technical assistance. This work was supported by fellowships from the Wenner-Gren Foundation and the af Jochnick Foundation, Sweden to C. B. J, the National MS Society and grants from the NIH to L. S and S. Y and a career transitional fellowship from the National Multiple Sclerosis Society (NMSS) to S. Y, a CIHR grant MOP81382 to F. M. V. R, and NIH grants AG009521, HD018179, AG020961, AG024987, the McKnight Foundation, and the Baxter Foundation to H. M. B.

Author information

Authors and Affiliations

Authors

Contributions

C. B. J. planned the project, executed all experiments, generated confocal microscopy images, analysed the data, wrote the manuscript and put together the figures; S. Y. participated in the EAE experiment; K. K. carried out the bone marrow transplantations and helped with the parabiosis; C. H. assisted with the immunohistochemistry and generated confocal microscopy images; R. D. contributed to the data analysis and to the writing of the manuscript; S. Y. C. generated single HSC-transplanted mice. L. S. and F. M. V. R. contributed to the writing of the manuscript; H. M. B. planned the project, analysed the data and wrote the manuscript.

Corresponding authors

Correspondence to Clas B. Johansson or Helen M. Blau.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Figures S1, S2, S3, S4 and Supplemental Table S1 (PDF 745 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Johansson, C., Youssef, S., Koleckar, K. et al. Extensive fusion of haematopoietic cells with Purkinje neurons in response to chronic inflammation. Nat Cell Biol 10, 575–583 (2008). https://doi.org/10.1038/ncb1720

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1720

This article is cited by

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