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Bone marrow–derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation

Abstract

Recent studies have suggested that bone marrow cells might possess a much broader differentiation potential than previously appreciated. In most cases, the reported efficiency of such plasticity has been rather low and, at least in some instances, is a consequence of cell fusion. After myocardial infarction, however, bone marrow cells have been suggested to extensively regenerate cardiomyocytes through transdifferentiation. Although bone marrow–derived cells are already being used in clinical trials, the exact identity, longevity and fate of these cells in infarcted myocardium have yet to be investigated in detail. Here we use various approaches to induce acute myocardial injury and deliver transgenically marked bone marrow cells to the injured myocardium. We show that unfractionated bone marrow cells and a purified population of hematopoietic stem and progenitor cells efficiently engraft within the infarcted myocardium. Engraftment was transient, however, and hematopoietic in nature. In contrast, bone marrow–derived cardiomyocytes were observed outside the infarcted myocardium at a low frequency and were derived exclusively through cell fusion.

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Figure 1: Evaluation of hematopoietic stem and progenitor cell mobilization after myocardial infarction.
Figure 2: Direct transplantation and engraftment of β-actin/GFP-transgenic bone marrow cells into infarcted myocardium.
Figure 3: Engraftment of cytokine-mobilized β-actin/GFP-transgenic bone marrow cells in infarcted myocardium.
Figure 4: Bone marrow–derived GFP+ cardiomyocytes in viable myocardium.
Figure 5: Fusion of bone marrow–derived cells with cardiomyocytes in viable myocardium, 28 d after LCA ligation and cytokine mobilization of Rosa26 (lacZ-transgenic) mice reconstituted with whole β-actin/GFP-transgenic bone marrow cells.

References

  1. Lagasse, E., Shizuru, J.A., Uchida, N., Tsukamoto, A. & Weissman, I.L. Toward regenerative medicine. Immunity 14, 425–436 (2001).

    Article  CAS  Google Scholar 

  2. Gussoni, E. et al. Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature 401, 390–394 (1999).

    CAS  PubMed  Google Scholar 

  3. Petersen, B.E. et al. Bone marrow as a potential source of hepatic oval cells. Science 284, 1168–1170 (1999).

    Article  CAS  Google Scholar 

  4. 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).

    Article  CAS  Google Scholar 

  5. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Jackson, K.A. et al. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J. Clin. Invest. 107, 1395–1402 (2001).

    Article  CAS  Google Scholar 

  9. Kawada, H. & Ogawa, M. Bone marrow origin of hematopoietic progenitors and stem cells in murine muscle. Blood 98, 2008–2013 (2001).

    Article  CAS  Google Scholar 

  10. 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 

  11. Castro, R.F. et al. Failure of bone marrow cells to transdifferentiate into neural cells in vivo . Science 297, 1299 (2002).

    Article  CAS  Google Scholar 

  12. McKinney-Freeman, S.L. et al. Muscle-derived hematopoietic stem cells are hematopoietic in origin. Proc. Natl. Acad. Sci. USA 99, 1341–1346 (2002).

    Article  CAS  Google Scholar 

  13. Geiger, H. et al. Analysis of the hematopoietic potential of muscle-derived cells in mice. Blood 100, 721–723 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. 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 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  21. Wang, X. et al. Kinetics of liver repopulation after bone marrow transplantation. Am. J. Pathol. 161, 565–574 (2002).

    Article  Google Scholar 

  22. Quaini, F. et al. Chimerism of the transplanted heart. N. Engl. J. Med. 346, 5–15 (2002).

    Article  Google Scholar 

  23. Laflamme, M.A., Myerson, D., Saffitz, J.E. & Murry, C.E. Evidence for cardiomyocyte repopulation by extracardiac progenitors in transplanted human hearts. Circ. Res. 90, 634–640 (2002).

    Article  CAS  Google Scholar 

  24. 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 

  25. 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).

    Article  CAS  Google Scholar 

  26. Orlic, D. et al. Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc. Natl. Acad. Sci. USA 98, 10344–10349 (2001).

    Article  CAS  Google Scholar 

  27. Strauer, B.E. et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 106, 1913–1918 (2002).

    Article  Google Scholar 

  28. Assmus, B. et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI). Circulation 106, 3009–3017 (2002).

    Article  Google Scholar 

  29. Stamm, C. et al. Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet 361, 45–46 (2003).

    Article  Google Scholar 

  30. 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 

  31. Bryder, D. & Jacobsen, S.E. Interleukin-3 supports expansion of long-term multilineage repopulating activity after multiple stem cell divisions in vitro . Blood 96, 1748–1755 (2000).

    CAS  PubMed  Google Scholar 

  32. Okabe, M., Ikawa, M., Kominami, K., Nakanishi, T. & Nishimune, Y. 'Green mice' as a source of ubiquitous green cells. FEBS Lett. 407, 313–319 (1997).

    Article  CAS  Google Scholar 

  33. Osawa, M., Hanada, K., Hamada, H. & Nakauchi, H. Long-term lymphohematopoietic reconstitution by a single CD34lo/neg hematopoietic stem cell. Science 273, 242–245 (1996).

    Article  CAS  Google Scholar 

  34. Kronenwett, R., Martin, S. & Haas, R. The role of cytokines and adhesion molecules for mobilization of peripheral blood stem cells. Stem Cells 18, 320–330 (2000).

    Article  CAS  Google Scholar 

  35. Bensinger, W.I. & Storb, R. Allogenic peripheral blood stem cell transplantation. Rev. Clin. Exp. Hematol. 5, 67–86 (2001).

    Article  CAS  Google Scholar 

  36. Zambrowicz, B.P. et al. Disruption of overlapping transcripts in the ROSA beta geo 26 gene trap strain leads to widespread expression of β-galactosidase in mouse embryos and hematopoietic cells. Proc. Natl. Acad. Sci. USA 94, 3789–3794 (1997).

    Article  CAS  Google Scholar 

  37. Fleischmann, M. et al. Cardiac specific expression of the green fluorescent protein during early murine embryonic development. FEBS Lett. 440, 370–376 (1998).

    Article  CAS  Google Scholar 

  38. Roell, W. et al. Cellular cardiomyoplasty improves survival after myocardial injury. Circulation 105, 2435–2441 (2002).

    Article  Google Scholar 

  39. Agbulut, O. et al. Temporal patterns of bone marrow cell differentiation following transplantation in doxorubicin-induced cardiomyopathy. Cardiovasc. Res. 58, 451–459 (2003).

    Article  CAS  Google Scholar 

  40. Oh, H. et al. Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc. Natl. Acad. Sci. USA 100, 12313–12318 (2003).

    Article  CAS  Google Scholar 

  41. Kang, H.-J. et al. Effects of intracoronary infusion of peripheral blood stem-cells mobilised with granulocyte-colony stimulating factor on left ventricular systolic function and restenosis after coronary stenting in myocardial infarction: the MAGIC cell randomised clinical trial. Lancet 363, 751–756 (2004).

    Article  CAS  Google Scholar 

  42. Matsubara, H. Risk to the coronary arteries of intracoronary stem cell infusion and G-CSF cytokine therapy. Lancet 363, 746–747 (2004).

    Article  Google Scholar 

  43. Shintani, S. et al. Mobilization of endothelial progenitor cells in patients with acute myocardial infarction. Circulation 103, 2776–2779 (2001).

    Article  CAS  Google Scholar 

  44. Balsam, L.B. et al. Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature 428, 664–668 (2004).

    Article  Google Scholar 

  45. Murry, C.E. et al. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 428, 668–673 (2004).

    Article  Google Scholar 

  46. Roell, W. et al. Cellular cardiomyoplasty in a transgenic mouse model. Transplantation 73, 462–465 (2002).

    Article  Google Scholar 

  47. Borge, O.J., Adolfsson, J. & Jacobsen, A.M. Lymphoid-restricted development from multipotent candidate murine stem cells: distinct and complimentary functions of the c-kit and flt3- ligands. Blood 94, 3781–3790 (1999).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank A. Björklund for fruitful discussions and expert advice on confocal microscopy data; L. Wittman, E. Chodkiewicz, Y. Duan and Z. Wu for expert technical assistance; and the FACS Facility at Lund Strategic Research Center for Stem Cell Biology and Cell Therapy for assistance with cell sorting. This work was supported by 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) 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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Correspondence to Sten Eirik W Jacobsen.

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Nygren, J., Jovinge, S., Breitbach, M. et al. Bone marrow–derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nat Med 10, 494–501 (2004). https://doi.org/10.1038/nm1040

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