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Myeloid and lymphoid contribution to non-haematopoietic lineages through irradiation-induced heterotypic cell fusion

Nature Cell Biology volume 10, pages 584–592 (2008)Cite this article

Abstract

Recent studies have suggested that regeneration of non-haematopoietic cell lineages can occur through heterotypic cell fusion1,2,3 with haematopoietic cells of the myeloid lineage2,3,4,5,6. Here we show that lymphocytes also form heterotypic-fusion hybrids with cardiomyocytes, skeletal muscle, hepatocytes and Purkinje neurons. However, through lineage fate-mapping we demonstrate that such in vivo fusion of lymphoid and myeloid blood cells does not occur to an appreciable extent in steady-state adult tissues or during normal development. Rather, fusion of blood cells with different non-haematopoietic cell types is induced by organ-specific injuries or whole-body irradiation1,2,3,4,5,6,7,8,9,10, which has been used in previous studies to condition recipients of bone marrow transplants. Our findings demonstrate that blood cells of the lymphoid and myeloid lineages contribute to various non-haematopoietic tissues by forming rare fusion hybrids, but almost exclusively in response to injuries or inflammation.

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Figure 1: Both lymphoid and myeloid blood lineages contribute to non-haematopoietic cells through heterotypic cell fusion.
Figure 2: Contribution to heart, skeletal muscle and brain following tissue specific injuries.
Figure 3: Evaluation of heterotypic blood cell fusion with cardiomyocytes, skeletal muscle fibres, hepatocytes and Purkinje neurons in adult mice 9 weeks after bone marrow transplantation.
Figure 4: Lymphocytes contribute to hepatocytes and Purkinje neurons following in utero transplantation but not during normal embryonic development.

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Acknowledgements

We thank L. Wittman, U. Jarl, A. Josefsson and E. Cordero for reliable technical assistance. This work was supported by the Swedish Childhood Cancer Foundation, the Swedish Heart Lung Foundation, The Juvenile Diabetes Research Foundation, the Swedish Diabetes Foundation, the Swedish Research Council, the Deutsche Forschungsgemeinschaft (FL 276/4–2/3) and the Scientific Exchange Program, North Rhine Westphalia-Sweden. The Lund Stem Cell Center is supported by a Center of Excellence grant in life sciences from the Swedish Foundation for Strategic Research.

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Authors and Affiliations

  1. Hematopoietic Stem Cell Laboratory, Lund University, BMC B10, Klinikgatan 26, Lund, 221 84, Sweden

    Jens M. Nygren, Karina Liuba, Lina Thorén, Stefan Jovinge & Sten Eirik W. Jacobsen

  2. Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, BMC B10, Klinikgatan 26, Lund, 221 84, Sweden

    Jens M. Nygren, Karina Liuba, Simon Stott, Lina Thorén, Deniz Kirik, Anders Björklund, Claus Nerlov, Stefan Jovinge & Sten Eirik W. Jacobsen

  3. Division of Immunology, Department of Experimental Medical Science, Lund University, BMC I13, Sölvegatan 19, Lund, 221 84, Sweden

    Jens M. Nygren

  4. Institute of Physiology I, Life & Brain Center, University of Bonn, Sigmund-Freud-Str. 25, Bonn, 53105, Germany

    Martin Breitbach, Caroline Geisen, Philipp Sasse & Bernd K. Fleischmann

  5. Division of Neurobiology, Wallenberg Neuroscience Center, Lund University, Sölvegatan 17, Lund, 223 62, Sweden

    Simon Stott, Deniz Kirik & Anders Björklund

  6. Department of Cardiac Surgery, University of Bonn, Sigmund-Freud-Str. 25, Bonn, 53105, Germany

    Wilhelm Roell

  7. EMBL Monterotondo, Mouse Biology Unit, Via Ramarini 32, I-00016, Monterotondo, Italy

    Claus Nerlov

  8. Department of Cardiology, Heart- and Lung Division, Coronary Program, Lund University Hosp Lund University, Lund, 221 85, Sweden

    Stefan Jovinge

  9. Haematopoietic Stem Cell Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headington, OX3 9DS, UK

    Sten Eirik W. Jacobsen

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Contributions

J. M. N., K. L., L. T., C. N. and S. E. W. J. designed, performed and analysed bone marrow transplantation models; J. M. N., M. B., B. F. K. and S. E. W. J. designed, performed and analysed muscle injury models. J. M. N., S. S., D. K., A. B. and S. E. W. J. designed, performed and analysed brain injury models; J. M. N., M. B., W. R., B. K. J., S. J. and S. E. W. J. designed, performed and analysed heart injury models. J. M. N., K. L., S. J. and S. E. W. J. designed, performed and analysed irradiation injury models; J. M. N., M. B., S. S., C. G., P. S., B. K. F., S. J. and S. E. W. J. designed, performed and analysed fused cell characterization; J. M. N., K. L., S. S., D. K., A. B., S. J. and S. E. W. J. performed and analysed fetal and neonatal transplantation models; J. M. N. and S. E. W. J. wrote the manuscript and K. L., M. B., S. S. L. T., W. R., C. G., P. S., D. K., A. B., C. N., B. K. F. and S. J. reviewed the manuscript.

Corresponding author

Correspondence to Sten Eirik W. Jacobsen.

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Supplementary Figures S1, S2, S3, S4, S5, S6 and Supplemental Methods (PDF 1495 kb)

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Nygren, J., Liuba, K., Breitbach, M. et al. Myeloid and lymphoid contribution to non-haematopoietic lineages through irradiation-induced heterotypic cell fusion. Nat Cell Biol 10, 584–592 (2008). https://doi.org/10.1038/ncb1721

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