Mammalian heart renewal by pre-existing cardiomyocytes (original) (raw)

Nature volume 493, pages 433–436 (2013)Cite this article

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Abstract

Although recent studies have revealed that heart cells are generated in adult mammals, the frequency of generation and the source of new heart cells are not yet known. Some studies suggest a high rate of stem cell activity with differentiation of progenitors to cardiomyocytes1. Other studies suggest that new cardiomyocytes are born at a very low rate2,3,4, and that they may be derived from the division of pre-existing cardiomyocytes. Here we show, by combining two different pulse–chase approaches—genetic fate-mapping with stable isotope labelling, and multi-isotope imaging mass spectrometry—that the genesis of cardiomyocytes occurs at a low rate by the division of pre-existing cardiomyocytes during normal ageing, a process that increases adjacent to areas of myocardial injury. We found that cell cycle activity during normal ageing and after injury led to polyploidy and multinucleation, but also to new diploid, mononucleate cardiomyocytes. These data reveal pre-existing cardiomyocytes as the dominant source of cardiomyocyte replacement in normal mammalian myocardial homeostasis as well as after myocardial injury.

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Acknowledgements

We thank J. Gannon for surgical assistance; J. Lammerding and P. Isserman for assistance with microscopy and IP Lab software; and C. MacGillivray for histology; and J. C. Poczatek and Z. Kaufman for assistance with OpenMIMS Data Analysis and image data processing. S.E.S. is funded by the National Institutes of Health (NIH; F32 HL108570). M.L.S. is funded by the American Heart Association (AHA FTF), Future Leaders in Cardiovascular Medicine, Watkins Cardiovascular Leadership Award and the NIH (K08 DK090147). C.P.L. is funded by the NIH (EB001974 and AG034641) and the Ellison Medical Foundation (AG-SS-2215-08). R.T.L. is funded by the NIH (AG032977 and AG040019) and the Harvard Stem Cell Institute.

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Authors and Affiliations

  1. Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Cambridge, 02139, Massachusetts, USA
    Samuel E. Senyo, Matthew L. Steinhauser, Christie L. Pizzimenti, Vicky K. Yang, Lei Cai & Richard T. Lee
  2. INSERM U.759, Orsay, 91405, France
    Ting-Di Wu & Jean-Luc Guerquin-Kern
  3. Institut Curie, Laboratoire de Microscopie Ionique, Orsay, 91405, France
    Ting-Di Wu & Jean-Luc Guerquin-Kern
  4. National Resource for Imaging Mass Spectrometry, Cambridge, 02139, Massachusetts, USA
    Mei Wang & Claude P. Lechene
  5. Genetics Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Cambridge, 02139, Massachusetts, USA
    Mei Wang & Claude P. Lechene
  6. Harvard Stem Cell Institute, Cambridge, 02139, Massachusetts, USA
    Richard T. Lee

Authors

  1. Samuel E. Senyo
  2. Matthew L. Steinhauser
  3. Christie L. Pizzimenti
  4. Vicky K. Yang
  5. Lei Cai
  6. Mei Wang
  7. Ting-Di Wu
  8. Jean-Luc Guerquin-Kern
  9. Claude P. Lechene
  10. Richard T. Lee

Contributions

S.E.S., M.L.S. and R.T.L. designed the experiments. S.E.S., M.L.S. and V.K.Y. performed the experiments. L.C., C.L.P., V.K.Y., M.L.S. and S.E.S. performed histology. M.W. and S.E.S. operated the prototype nanoSIMS instrument. T.-D.W. operated the nanoSIMS instrument at Institut Curie with input from J.-L.G.K; S.E.S. and M.L.S. analysed the data, with input from C.P.L. and R.T.L. C.P.L. supervised all MIMS analyses and provided critical feedback at all junctures. S.E.S. and M.L.S. made the figures. S.E.S., M.L.S. and R.T.L. wrote the manuscript. All authors approved the manuscript.

Corresponding author

Correspondence toRichard T. Lee.

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The authors declare no competing financial interests.

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Senyo, S., Steinhauser, M., Pizzimenti, C. et al. Mammalian heart renewal by pre-existing cardiomyocytes.Nature 493, 433–436 (2013). https://doi.org/10.1038/nature11682

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Editorial Summary

Heart-cell replacement in the adult

There is controversy in the cardiovascular field regarding the extent of existing cardiomyocyte turnover versus progenitor cell contributions during mammalian cardiac homeostasis throughout adult life. This study takes a novel approach to settling the debate by using a combination of prospective labelling with the nitrogen-15 isotope and genetic pulse–chase to measure DNA synthesis in the adult mammalian heart. The authors conclude that during normal ageing, preexisting cardiomyocytes are the dominant source of cardiomyocyte replacement in normal mammalian myocardial homeostasis, a process that is increased fivefold during recovery from myocardial infarction.