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Mammalian heart renewal by pre-existing cardiomyocytes

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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Figure 1: Use of MIMS to study cardiomyocyte turnover.
Figure 2: Cardiomyocyte DNA synthesis decreases with age.
Figure 3: New cardiomyocytes are derived from pre-existing cardiomyocytes during ageing.
Figure 4: Myocardial injury stimulates division of pre-existing cardiomyocytes.

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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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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.

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Correspondence to Richard 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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