title: In vivo activation of a conserved microRNA program induces mammalian heart regeneration.
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.
authors.affiliation: Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Aitor
authors.initials: A
authors.lastname: Aguirre
authors.affiliation: Center of Regenerative Medicine of Barcelona (CMRB), 08003 Barcelona, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Montserrat
authors.affiliation: International Center for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Zacchigna
authors.affiliation: Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Nivet
authors.affiliation: Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Hishida
authors.affiliation: Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Marie N
authors.initials: MN
authors.lastname: Krause
authors.affiliation: Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Leo
authors.initials: L
authors.lastname: Kurian
authors.affiliation: Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Ocampo
authors.affiliation: Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Vazquez-Ferrer
authors.affiliation: Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Concepcion
authors.initials: C
authors.lastname: Rodriguez-Esteban
authors.affiliation: Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Sachin
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, SR-11, La Jolla, CA 92037, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Moresco
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, SR-11, La Jolla, CA 92037, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.affiliation: Renal Division, Hospital Clinic, University of Barcelona, IDIBAPS, 08036 Barcelona, Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Campistol
authors.affiliation: Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Sancho-Martinez
authors.affiliation: International Center for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Giacca
authors.affiliation: Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: belmonte@salk.edu.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Izpisua Belmonte
mesh_terms: D000818:Animals; D054337:Cell Dedifferentiation / Q000235:genetics; D049109:Cell Proliferation; D015536:Down-Regulation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D016678:Genome; D006321:Heart / Q000502:physiology*; D006801:Humans; D008322:Mammals / Q000235:genetics*; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D012038:Regeneration / Q000235:genetics*; D015027:Zebrafish / Q000235:genetics
chemical_list: D035683:MicroRNAs