In vivo activation of a conserved microRNA program induces mammalian heart regeneration

Aitor Aguirre, Nuria Montserrat, Serena Zacchigna, Emmanuel Nivet, Tomoaki Hishida, Marie N. Krause, Leo Kurian, Alejandro Ocampo, Eric Vazquez-Ferrer, Concepcion Rodriguez-Esteban, Sachin Kumar, James J. Moresco, John R. Yates, Josep M. Campistol, Ignacio Sancho-Martinez, Mauro Giacca, Juan Carlos Izpisua Belmonte

Research output: Contribution to journalArticle

99 Scopus citations

Abstract

Heart failure is a leading cause of mortality and morbidity in the developed world, partly because mammals lack the ability to regenerate heart tissue. Whether this is due to evolutionary loss of regenerative mechanisms present in other organisms or to an inability to activate such mechanisms is currently unclear. Here we decipher mechanisms underlying heart regeneration in adult zebrafish and show that the molecular regulators of this response are conserved in mammals. We identified miR-99/100 and Let-7a/c and their protein targets smarca5 and fntb as critical regulators of cardiomyocyte dedifferentiation and heart regeneration in zebrafish. Although human and murine adult cardiomyocytes fail to elicit an endogenous regenerative response after myocardial infarction, we show that in vivo manipulation of this molecular machinery in mice results in cardiomyocyte dedifferentiation and improved heart functionality after injury. These data provide a proof of concept for identifying and activating conserved molecular programs to regenerate the damaged heart.

Original languageEnglish (US)
Pages (from-to)589-604
Number of pages16
JournalCell Stem Cell
Volume15
Issue number5
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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  • Cite this

    Aguirre, A., Montserrat, N., Zacchigna, S., Nivet, E., Hishida, T., Krause, M. N., Kurian, L., Ocampo, A., Vazquez-Ferrer, E., Rodriguez-Esteban, C., Kumar, S., Moresco, J. J., Yates, J. R., Campistol, J. M., Sancho-Martinez, I., Giacca, M., & Izpisua Belmonte, J. C. (2014). In vivo activation of a conserved microRNA program induces mammalian heart regeneration. Cell Stem Cell, 15(5), 589-604. https://doi.org/10.1016/j.stem.2014.10.003