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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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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.

Author information

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.

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

Authors
  1. Patrick C H Hsieh
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  2. Vincent F M Segers
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  4. Catherine MacGillivray
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  5. Joseph Gannon
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  6. Jeffery D Molkentin
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  7. Jeffrey Robbins
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  8. Richard T Lee
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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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