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Functional screening identifies miRNAs inducing cardiac regeneration

Author

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  • Ana Eulalio

    (Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB)
    Present address: Institute for Molecular Infection Biology (IMIB), University of Würzburg, D-97080 Würzburg, Germany.)

  • Miguel Mano

    (Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB))

  • Matteo Dal Ferro

    (Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB)
    Surgical and Health Sciences, University of Trieste, Trieste, Italy and Center for Translational Cardiology)

  • Lorena Zentilin

    (Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB))

  • Gianfranco Sinagra

    (Surgical and Health Sciences, University of Trieste, Trieste, Italy and Center for Translational Cardiology)

  • Serena Zacchigna

    (Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB))

  • Mauro Giacca

    (Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB))

Abstract

In mammals, enlargement of the heart during embryonic development is primarily dependent on the increase in cardiomyocyte numbers. Shortly after birth, however, cardiomyocytes stop proliferating and further growth of the myocardium occurs through hypertrophic enlargement of the existing myocytes. As a consequence of the minimal renewal of cardiomyocytes during adult life, repair of cardiac damage through myocardial regeneration is very limited. Here we show that the exogenous administration of selected microRNAs (miRNAs) markedly stimulates cardiomyocyte proliferation and promotes cardiac repair. We performed a high-content microscopy, high-throughput functional screening for human miRNAs that promoted neonatal cardiomyocyte proliferation using a whole-genome miRNA library. Forty miRNAs strongly increased both DNA synthesis and cytokinesis in neonatal mouse and rat cardiomyocytes. Two of these miRNAs (hsa-miR-590 and hsa-miR-199a) were further selected for testing and were shown to promote cell cycle re-entry of adult cardiomyocytes ex vivo and to promote cardiomyocyte proliferation in both neonatal and adult animals. After myocardial infarction in mice, these miRNAs stimulated marked cardiac regeneration and almost complete recovery of cardiac functional parameters. The miRNAs identified hold great promise for the treatment of cardiac pathologies consequent to cardiomyocyte loss.

Suggested Citation

  • Ana Eulalio & Miguel Mano & Matteo Dal Ferro & Lorena Zentilin & Gianfranco Sinagra & Serena Zacchigna & Mauro Giacca, 2012. "Functional screening identifies miRNAs inducing cardiac regeneration," Nature, Nature, vol. 492(7429), pages 376-381, December.
  • Handle: RePEc:nat:nature:v:492:y:2012:i:7429:d:10.1038_nature11739
    DOI: 10.1038/nature11739
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    Cited by:

    1. Slobodan Vukicevic & Andrea Colliva & Vera Kufner & Valentina Martinelli & Silvia Moimas & Simone Vodret & Viktorija Rumenovic & Milan Milosevic & Boris Brkljacic & Diana Delic-Brkljacic & Ricardo Cor, 2022. "Bone morphogenetic protein 1.3 inhibition decreases scar formation and supports cardiomyocyte survival after myocardial infarction," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Yu Chen & Shuai Liu & Yunsong Liang & Yutong He & Qian Li & Jiamian Zhan & Honghao Hou & Xiaozhong Qiu, 2024. "Single dose of intravenous miR199a-5p delivery targeting ischemic heart for long-term repair of myocardial infarction," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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