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Meis1 regulates postnatal cardiomyocyte cell cycle arrest

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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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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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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