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.

Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium

Abstract

Under conditions of tissue injury, myocardial replication and regeneration have been reported1. A growing number of investigators have implicated adult bone marrow (BM) in this process, suggesting that marrow serves as a reservoir for cardiac precursor cells2,3,4,5,6. It remains unclear which BM cell(s) can contribute to myocardium, and whether they do so by transdifferentiation or cell fusion. Here, we studied the ability of c-kit-enriched BM cells, Lin- c-kit+ BM cells and c-kit+ Thy1.1lo Lin- Sca-1+ long-term reconstituting haematopoietic stem cells to regenerate myocardium in an infarct model. Cells were isolated from transgenic mice expressing green fluorescent protein (GFP) and injected directly into ischaemic myocardium of wild-type mice. Abundant GFP+ cells were detected in the myocardium after 10 days, but by 30 days, few cells were detectable. These GFP+ cells did not express cardiac tissue-specific markers, but rather, most of them expressed the haematopoietic marker CD45 and myeloid marker Gr-1. We also studied the role of circulating cells in the repair of ischaemic myocardium using GFP+–GFP- parabiotic mice. Again, we found no evidence of myocardial regeneration from blood-borne partner-derived cells. Our data suggest that even in the microenvironment of the injured heart, c-kit-enriched BM cells, Lin- c-kit+ BM cells and c-kit+ Thy1.1lo Lin- Sca-1+ long-term reconstituting haematopoietic stem cells adopt only traditional haematopoietic fates.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: BM cells injected into ischaemic myocardium do not adopt cardiac, smooth muscle, or endothelial phenotypes.
Figure 2: Haematopoietic phenotype of BM cells injected into ischaemic myocardium.
Figure 3: BM cells injected into ischaemic myocardium differentiate into granulocytes.
Figure 4: Chimaerism of cardiac tissue in non-transgenic parabiotic partners 8 weeks after cardiac injury and parabiosis.

References

  1. Beltrami, A. P. et al. Evidence that human cardiac myocytes divide after myocardial infarction. N. Engl. J. Med. 344, 1750–1757 (2001)

    CAS  Article  Google Scholar 

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

    Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  4. Toma, C., Pittenger, M. F., Cahill, K. S., Byrne, B. J. & Kessler, P. D. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation 105, 93–98 (2002)

    Article  Google Scholar 

  5. Deb, A. et al. Bone marrow-derived cardiomyocytes are present in adult human heart: a study of gender-mismatched bone marrow transplantation patients. Circulation 107, 1247–1249 (2003)

    Article  Google Scholar 

  6. 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)

    ADS  CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

  8. 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 

  9. 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)

    ADS  CAS  Article  Google Scholar 

  10. 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 

  11. 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 

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

    ADS  CAS  Article  Google Scholar 

  13. 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)

    ADS  CAS  Article  Google Scholar 

  14. 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)

    CAS  Article  Google Scholar 

  15. Tse, H. F. et al. Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet 361, 47–49 (2003)

    Article  Google Scholar 

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

    Article  Google Scholar 

  17. Wright, D. E. et al. Cyclophosphamide/granulocyte colony-stimulating factor causes selective mobilization of bone marrow hematopoietic stem cells into the blood after M phase of the cell cycle. Blood 97, 2278–2285 (2001)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank G. Hoyt for technical assistance with animal surgery, and V. Mariano and L. Hildalgo for animal care. This work was supported by the Falk Cardiovascular research fund (R.C.R.) and an NIH grant (I.L.W.). L.B.B. was supported by Thoracic Surgery Foundation Nina Starr Braunwald Research Training Fellowship; A.J.W. was supported by an American Cancer Society grant and the Frederick Frank/Lehman Brothers, Inc. Irvington Institute Fellowship; J.L.C. was supported by a NIH Training Grant in Molecular and Cellular Immunobiology; and T.K. was supported by a German Research Society Training Grant.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Robert C. Robbins.

Ethics declarations

Competing interests

Affiliations that might be perceived to have biased this work are as follows: (1) I.L.W. owns significant Amgen stock from participation on their scientific advisory board; (2) I.L.W. co-founded and consulted for Systemix, is a co-founder and director of Stem Cells, Inc., and recently co-founded Cellerant. None of these is involved in cardiac regeneration or the identification of bone marrow myocardial precursor cells.

Supplementary information

Supplementary Figure 1

Cardiac tissue stained with Masson’s trichrome stain at 10 days and 30 days after infarction (JPG 71 kb)

Supplementary Figure 2

Lymphoid differentiation of LT-HSCs injected into ischemic myocardium. (JPG 20 kb)

Supplementary Figure 3

Cardiac tissue stained with Masson’s trichrome stain 6 weeks after infarction. (JPG 71 kb)

Supplementary Figure Legends (DOC 20 kb)

Supplementary Tables

Table 1: Echocardiographic function of cell-treated vs. saline-treated infarcted hearts at 2 weeks and 6 weeks post-injury; Table 2: Hemodynamic parameters of cell-treated and saline-treated infarcted animals 6 weeks after infarction; Table 3: Hematopoietic chimerism in parabiotic pairs. (DOC 38 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Balsam, L., Wagers, A., Christensen, J. et al. Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature 428, 668–673 (2004). https://doi.org/10.1038/nature02460

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature02460

This article is cited by

Comments

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.

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