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Meis1 regulates postnatal cardiomyocyte cell cycle arrest

Nature volume 497, pages 249–253 (2013)Cite this article

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Abstract

The neonatal mammalian heart is capable of substantial regeneration following injury through cardiomyocyte proliferation1,2. However, this regenerative capacity is lost by postnatal day 7 and the mechanisms of cardiomyocyte cell cycle arrest remain unclear. The homeodomain transcription factor Meis1 is required for normal cardiac development but its role in cardiomyocytes is unknown3,4. Here we identify Meis1 as a critical regulator of the cardiomyocyte cell cycle. Meis1 deletion in mouse cardiomyocytes was sufficient for extension of the postnatal proliferative window of cardiomyocytes, and for re-activation of cardiomyocyte mitosis in the adult heart with no deleterious effect on cardiac function. In contrast, overexpression of Meis1 in cardiomyocytes decreased neonatal myocyte proliferation and inhibited neonatal heart regeneration. Finally, we show that Meis1 is required for transcriptional activation of the synergistic CDK inhibitors p15, p16 and p21. These results identify Meis1 as a critical transcriptional regulator of cardiomyocyte proliferation and a potential therapeutic target for heart regeneration.

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Figure 1: Expression profile of Meis1 in the heart.
Figure 2: Cardiomyocyte proliferation at P14 following Meis1 deletion.
Figure 3: Inducible deletion of Meis1 in cardiomyocytes.
Figure 4: Meis1 overexpression in the heart limits neonatal heart regeneration following myocardial infarction.

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References

  1. Porrello, E. R. et al. Transient regenerative potential of the neonatal mouse heart. Science 331, 1078–1080 (2011)

    Article  ADS  CAS  Google Scholar 

  2. Porrello, E. R. et al. Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family. Proc. Natl Acad. Sci. USA 110, 187–192 (2013)

    Article  ADS  CAS  Google Scholar 

  3. Paige, S. L. et al. A temporal chromatin signature in human embryonic stem cells identifies regulators of cardiac development. Cell 151, 221–232 (2012)

    Article  CAS  Google Scholar 

  4. Wamstad, J. A. et al. Dynamic and coordinated epigenetic regulation of developmental transitions in the cardiac lineage. Cell 151, 206–220 (2012)

    Article  CAS  Google Scholar 

  5. Bergmann, O. et al. Evidence for cardiomyocyte renewal in humans. Science 324, 98–102 (2009)

    Article  ADS  CAS  Google Scholar 

  6. Hsieh, P. C. et al. Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury. Nature Med. 13, 970–974 (2007)

    Article  CAS  Google Scholar 

  7. Heallen, T. et al. Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science 332, 458–461 (2011)

    Article  ADS  CAS  Google Scholar 

  8. Kikuchi, K. et al. Primary contribution to zebrafish heart regeneration by gata4+ cardiomyocytes. Nature 464, 601–605 (2010)

    Article  ADS  CAS  Google Scholar 

  9. Jopling, C. et al. Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature 464, 606–609 (2010)

    Article  ADS  CAS  Google Scholar 

  10. Azcoitia, V., Aracil, M., Martinez, A. C. & Torres, M. The homeodomain protein Meis1 is essential for definitive hematopoiesis and vascular patterning in the mouse embryo. Dev Biol 280, 307–320 (2005)

    Article  CAS  Google Scholar 

  11. Hisa, T. et al. Hematopoietic, angiogenic and eye defects in Meis1 mutant animals. EMBO J. 23, 450–459 (2004)

    Article  CAS  Google Scholar 

  12. Imamura, T. et al. Frequent co-expression of HoxA9 and Meis1 genes in infant acute lymphoblastic leukaemia with MLL rearrangement. Br. J. Haematol. 119, 119–121 (2002)

    Article  CAS  Google Scholar 

  13. Kocabas, F. et al. Meis1 regulates the metabolic phenotype and oxidant defense of hematopoietic stem cells. Blood 120, 4963–4972 (2012)

    Article  CAS  Google Scholar 

  14. Shen, W. F. et al. AbdB-like Hox proteins stabilize DNA binding by the Meis1 homeodomain proteins. Mol. Cell. Biol. 17, 6448–6458 (1997)

    Article  MathSciNet  CAS  Google Scholar 

  15. Bersell, K., Arab, S., Haring, B. & Kuhn, B. Neuregulin1/ErbB4 signaling induces cardiomyocyte proliferation and repair of heart injury. Cell 138, 257–270 (2009)

    Article  CAS  Google Scholar 

  16. Pasumarthi, K. B., Nakajima, H., Nakajima, H. O., Soonpaa, M. H. & Field, L. J. Targeted expression of cyclin D2 results in cardiomyocyte DNA synthesis and infarct regression in transgenic mice. Circ. Res. 96, 110–118 (2005)

    Article  CAS  Google Scholar 

  17. Gude, N. et al. Akt promotes increased cardiomyocyte cycling and expansion of the cardiac progenitor cell population. Circ. Res. 99, 381–388 (2006)

    Article  CAS  Google Scholar 

  18. Sdek, P. et al. Rb and p130 control cell cycle gene silencing to maintain the postmitotic phenotype in cardiac myocytes. J. Cell Biol. 194, 407–423 (2011)

    Article  CAS  Google Scholar 

  19. Pasumarthi, K. B. & Field, L. J. Cardiomyocyte cell cycle regulation. Circ. Res. 90, 1044–1054 (2002)

    Article  CAS  Google Scholar 

  20. Walsh, S., Ponten, A., Fleischmann, B. K. & Jovinge, S. Cardiomyocyte cell cycle control and growth estimation in vivo–an analysis based on cardiomyocyte nuclei. Cardiovasc. Res. 86, 365–373 (2010)

    Article  CAS  Google Scholar 

  21. Poolman, R. A., Gilchrist, R. & Brooks, G. Cell cycle profiles and expressions of p21CIP1 AND P27KIP1 during myocyte development. Int. J. Cardiol. 67, 133–142 (1998)

    Article  CAS  Google Scholar 

  22. MacLellan, W. R. et al. Overlapping roles of pocket proteins in the myocardium are unmasked by germ line deletion of p130 plus heart-specific deletion of Rb. Mol. Cell. Biol. 25, 2486–2497 (2005)

    Article  CAS  Google Scholar 

  23. Simsek, T. et al. The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell 7, 380–390 (2010)

    Article  CAS  Google Scholar 

  24. Smart, N. et al. De novo cardiomyocytes from within the activated adult heart after injury. Nature 474, 640–644 (2011)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  26. Mollova, M. et al. Cardiomyocyte proliferation contributes to heart growth in young humans. Proc. Natl Acad. Sci. USA 110, 1446–1451 (2013)

    Article  ADS  CAS  Google Scholar 

  27. Senyo, S. E. et al. Mammalian heart renewal by pre-existing cardiomyocytes. Nature 493, 433–436 (2013)

    Article  ADS  CAS  Google Scholar 

  28. Eulalio, A. et al. Functional screening identifies miRNAs inducing cardiac regeneration. Nature 492, 376–381 (2012)

    Article  ADS  CAS  Google Scholar 

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Acknowledgements

We thank J. Shelton for help with histology, J. Cabrera for help with figures, N. Copeland and N. Jenkins for providing the Meis1 KO mice, S. Das for statistics consultation, K. Luby-Phelps for help with microscopy, A. Bugde for confocal assistance, D. Farrar for discussions, H. Nguyen for help with echocardiography, as well as K. Sheth, A. Mercadel and Z. Sadek for technical assistance. This work is supported by grants from the American Heart Association (Grant in Aid) (H.A.S.), the Gilead Research Scholars Program in Cardiovascular Disease (H.A.S.), the Foundation for Heart Failure Research, NY, and the National Institutes of Health (1R01HL115275-01) (H.A.S.).

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Author notes

  1. Ahmed I. Mahmoud, Fatih Kocabas and Shalini A. Muralidhar: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, 75390, Texas, USA

    Ahmed I. Mahmoud, Fatih Kocabas, Shalini A. Muralidhar, Wataru Kimura, Suwannee Thet & Hesham A. Sadek

  2. School of Medicine, Ain Shams University, Cairo, 1156, Egypt

    Ahmed S. Koura

  3. School of Biomedical Sciences, The University of Queensland, St Lucia, 4072, Queensland, Australia

    Enzo R. Porrello

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  1. Ahmed I. Mahmoud
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Contributions

A.I.M, F.K., S.A.M., E.R.P. and H.A.S. designed the experiments. A.I.M., F.K., S.A.M., W.K. and S.T. performed the experiments. A.I.M., F.K., S.A.M., A.S.K., E.R.P. and H.A.S. analysed the data. A.I.M., F.K., S.A.M. and H.A.S. made the figures. A.I.M. and H.A.S. wrote the manuscript. All authors approved the manuscript.

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Correspondence to Hesham A. Sadek.

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The authors declare no competing financial interests.

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Mahmoud, A., Kocabas, F., Muralidhar, S. et al. Meis1 regulates postnatal cardiomyocyte cell cycle arrest. Nature 497, 249–253 (2013). https://doi.org/10.1038/nature12054

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