Functional screening identifies miRNAs inducing cardiac regeneration

Ana Eulalio, Miguel Mano, Matteo Dal Ferro, Lorena Zentilin, Gianfranco Sinagra, Serena Zacchigna and Mauro Giacca ()
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Ana Eulalio: Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB)
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)
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)

Nature, 2012, vol. 492, issue 7429, 376-381

Abstract: 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.

Date: 2012
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DOI: 10.1038/nature11739

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