A microRNA program regulates the balance between cardiomyocyte hyperplasia and hypertrophy and stimulates cardiac regeneration

Andrea Raso, Ellen Dirkx, Vasco Sampaio-Pinto, H. (Hamid) el Azzouzi, Ryan J. Cubero, Daniel W. Sorensen, Lara Ottaviani, Servé Olieslagers, Manon M. Huibers, Roel de Weger, Sailay Siddiqi, Silvia Moimas, Consuelo Torrini, Lorena Zentillin, Luca Braga, Diana S. Nascimento, Paula A. da Costa Martins, Jop H. van Berlo, Serena Zacchigna, Mauro GiaccaLeon J. De Windt*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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.

Original languageEnglish
Article number4808
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - 10 Aug 2021

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