RT Journal Article
SR Electronic
T1 A microRNA program controls the transition of cardiomyocyte hyperplasia to hypertrophy and stimulates mammalian cardiac regeneration
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.02.25.432908
DO 10.1101/2021.02.25.432908
A1 Andrea Raso
A1 Ellen Dirkx
A1 Vasco Sampaio-Pinto
A1 Hamid el Azzouzi
A1 Ryan J. Cubero
A1 Daniel W. Sorensen
A1 Lara Ottaviani
A1 Servé Olieslagers
A1 Manon M. Huibers
A1 Roel de Weger
A1 Sailay Siddiqi
A1 Silvia Moimas
A1 Consuelo Torrini
A1 Lorena Zentillin
A1 Luca Braga
A1 Paula A. da Costa Martins
A1 Jop H. van Berlo
A1 Serena Zacchigna
A1 Mauro Giacca
A1 Leon J. De Windt
YR 2021
UL http://biorxiv.org/content/early/2021/02/25/2021.02.25.432908.abstract
AB Myocardial regeneration is restricted to early postnatal life, when mammalian cardiomyocytes still retain the ability to proliferate. The molecular cues that induce cell cycle arrest of neonatal cardiomyocytes towards terminally differentiated adult heart muscle cells remain obscure. Here we report that the miR-106b∼25 cluster is higher expressed in the early postnatal myocardium and decreases in expression towards adulthood, especially under conditions of overload, and orchestrates the transition of cardiomyocyte hyperplasia towards cell cycle arrest and hypertrophy by virtue of its targetome. In line, gene delivery of miR-106b∼25 to the mouse heart provokes cardiomyocyte proliferation by targeting a network of negative cell cycle regulators including E2f5, Cdkn1c, Ccne1 and Wee1. Conversely, gene-targeted miR-106b∼25 null mice display spontaneous hypertrophic remodeling and exaggerated remodeling to overload by derepression of the prohypertrophic transcription factors Hand2 and Mef2d. Taking advantage of the regulatory function of miR-106b∼25 on cardiomyocyte hyperplasia and hypertrophy, viral gene delivery of miR-106b∼25 provokes nearly complete regeneration of the adult myocardium after ischemic injury. Our data demonstrate that exploitation of conserved molecular programs can enhance the regenerative capacity of the injured heart.Competing Interest StatementE.D., M.G. and L.D.W filed the data in the manuscript for patent protection. P.D.C.M. and L.D.W. are co-founders and stockholders of Mirabilis Therapeutics BV.