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Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury

Nature Medicine volume 13, pages 970–974 (2007)Cite this article

Abstract

An emerging concept is that the mammalian myocardium has the potential to regenerate, but that regeneration might be too inefficient to repair the extensive myocardial injury that is typical of human disease1,2,3,4,5,6,7,8. However, the degree to which stem cells or precursor cells contribute to the renewal of adult mammalian cardiomyocytes remains controversial. Here we report evidence that stem cells or precursor cells contribute to the replacement of adult mammalian cardiomyocytes after injury but do not contribute significantly to cardiomyocyte renewal during normal aging. We generated double-transgenic mice to track the fate of adult cardiomyocytes in a 'pulse-chase' fashion: after a 4-OH-tamoxifen pulse, green fluorescent protein (GFP) expression was induced only in cardiomyocytes, with 82.7% of cardiomyocytes expressing GFP. During normal aging up to one year, the percentage of GFP+ cardiomyocytes remained unchanged, indicating that stem or precursor cells did not refresh uninjured cardiomyocytes at a significant rate during this period of time. By contrast, after myocardial infarction or pressure overload, the percentage of GFP+ cardiomyocytes decreased from 82.8% in heart tissue from sham-treated mice to 67.5% in areas bordering a myocardial infarction, 76.6% in areas away from a myocardial infarction, and 75.7% in hearts subjected to pressure overload, indicating that stem cells or precursor cells had refreshed the cardiomyocytes.

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Figure 1: Generation of MerCreMer-ZEG mice for genetic fate mapping of adult mammalian cardiomyocytes.
Figure 2: Adult mammalian cardiomyocytes are not detectably replaced by stem or progenitor cells during normal aging.
Figure 3: Stem or progenitor cells replenish adult mammalian cardiomyocytes after myocardial injury.

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References

  1. 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 

  2. Beltrami, A.P. et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114, 763–776 (2003).

    Article  CAS  Google Scholar 

  3. Oh, H. et al. Cardiac muscle plasticity in adult and embryo by heart-derived progenitor cells. Ann. NY Acad. Sci. 1015, 182–189 (2004).

    Article  Google Scholar 

  4. Yoon, Y.S. et al. Clonally expanded novel multipotent stem cells from human bone marrow regenerate myocardium after myocardial infarction. J. Clin. Invest. 115, 326–338 (2005).

    Article  CAS  Google Scholar 

  5. Winitsky, S.O. et al. Adult murine skeletal muscle contains cells that can differentiate into beating cardiomyocytes in vitro. PLoS Biol. 3, e87 (2005).

    Article  Google Scholar 

  6. Laugwitz, K.L. et al. Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 433, 647–653 (2005).

    Article  CAS  Google Scholar 

  7. Becker, R.O., Chapin, S. & Sherry, R. Regeneration of the ventricular myocardium in amphibians. Nature 248, 145–147 (1974).

    Article  CAS  Google Scholar 

  8. Poss, K.D., Wilson, L.G. & Keating, M.T. Heart regeneration in zebrafish. Science 298, 2188–2190 (2002).

    Article  CAS  Google Scholar 

  9. Dor, Y., Brown, J., Martinez, O.I. & Melton, D.A. Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429, 41–46 (2004).

    Article  CAS  Google Scholar 

  10. Sohal, D.S. et al. Temporally regulated and tissue-specific gene manipulations in the adult and embryonic heart using a tamoxifen-inducible Cre protein. Circ. Res. 89, 20–25 (2001).

    Article  CAS  Google Scholar 

  11. Novak, A., Guo, C., Yang, W., Nagy, A. & Lobe, C.G. Z/EG, a double reporter mouse line that expresses enhanced green fluorescent protein upon Cre-mediated excision. Genesis 28, 147–155 (2000).

    Article  CAS  Google Scholar 

  12. Fazel, S. et al. Cardioprotective c-kit+ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines. J. Clin. Invest. 116, 1865–1877 (2006).

    Article  CAS  Google Scholar 

  13. Ducharme, A. et al. Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction. J. Clin. Invest. 106, 55–62 (2000).

    Article  CAS  Google Scholar 

  14. Rockman, H.A. et al. Segregation of atrial-specific and inducible expression of an atrial natriuretic factor transgene in an in vivo murine model of cardiac hypertrophy. Proc. Natl. Acad. Sci. USA 88, 8277–8281 (1991).

    Article  CAS  Google Scholar 

  15. Hsieh, P.C., Davis, M.E., Gannon, J., MacGillivray, C. & Lee, R.T. Controlled delivery of PDGF-BB for myocardial protection using injectable self-assembling peptide nanofibers. J. Clin. Invest. 116, 237–248 (2006).

    Article  CAS  Google Scholar 

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Acknowledgements

P.C.H. was supported by a fellowship from the American Heart Association. V.F.M.S. was supported by a Ph.D. fellowship of the Research Foundation— Flanders (FWO) and by a Belgian American Educational Foundation research fellowship. M.E.D. was supported by an NRSA fellowship from NIH/NHLBI. This study was supported by NIH/NHLBI grant R01HL081404.

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Author notes

  1. Patrick C H Hsieh

    Present address: Present address: Institute of Clinical Medicine, National Cheng Kung University, Tainan City, Taiwan.,

  2. Patrick C H Hsieh and Vincent F M Segers: These authors contributed equally to this work.

Authors and Affiliations

  1. Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, 02139, Massachusetts, USA

    Patrick C H Hsieh, Vincent F M Segers, Michael E Davis, Catherine MacGillivray, Joseph Gannon & Richard T Lee

  2. Division of Molecular Cardiovascular Biology, Department of Pediatrics, Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, 45229, Ohio, USA

    Jeffery D Molkentin & Jeffrey Robbins

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  1. Patrick C H Hsieh
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Contributions

Experiments were designed by P.C.H., V.F.M.S., M.E.D., J.D.M., J.R. and R.T.L. MerCreMer-ZEG mice were generated by P.C.H. and V.F.M.S., surgeries were performed by P.C.H., J.G. and V.F.M.S., immunohistochemistry and immunofluorescence staining were performed by P.C.H., V.F.M.S. and C.M., GFP+ and β-galactosidase+ cells were counted by M.E.D. and data were analyzed by P.C.H., V.F.M.S. and R.T.L. The manuscript was written by V.F.M.S., P.H.C. and R.T.L. All authors discussed the results and commented on the manuscripts.

Corresponding author

Correspondence to Richard T Lee.

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The authors declare no competing financial interests.

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Supplementary Figs. 1–5, Supplementary Table 1 (PDF 558 kb)

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Hsieh, P., Segers, V., Davis, M. et al. Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury. Nat Med 13, 970–974 (2007). https://doi.org/10.1038/nm1618

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