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

Nature Medicine volume 10, pages 494–501 (2004)Cite this article

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.

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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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Authors and Affiliations

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

    Jens M Nygren, Stefan Jovinge, Petter Säwén, Jalal Taneera & Sten Eirik W Jacobsen

  2. Department of Cardiology, University Hospital MAS, Lund University, Malmö, 205 02, Sweden

    Stefan Jovinge

  3. Institute of Physiology I, University of Bonn, Argelander-Str. 2a, Bonn, 53115, Germany

    Martin Breitbach & Bernd K Fleischmann

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

    Wilhelm Röll

  5. Institute of Neurophysiology, University of Cologne, Robert-Koch-Str. 39, Cologne, 50931, Germany

    Jürgen Hescheler

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  1. Jens M Nygren
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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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