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

• Published in: Nature communications Vol. 12; no. 1; p. 4808
• Main Authors: Raso, Andrea, Dirkx, Ellen, Sampaio-Pinto, Vasco, el Azzouzi, Hamid, Cubero, Ryan J., Sorensen, Daniel W., Ottaviani, Lara, Olieslagers, Servé, Huibers, Manon M., de Weger, Roel, Siddiqi, Sailay, Moimas, Silvia, Torrini, Consuelo, Zentillin, Lorena, Braga, Luca, Nascimento, Diana S., da Costa Martins, Paula A., van Berlo, Jop H., Zacchigna, Serena, Giacca, Mauro, De Windt, Leon J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.08.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 14; 14/19; 38; 38/44; 38/91; 631/337/384/331; 692/4019/592/2725; Cardiac muscle; Cardiomyocytes; Cell cycle; Cell differentiation; Cell proliferation; Clusters; Derepression; Exploitation; Gene transfer; Heart; Humanities and Social Sciences; Hyperplasia; Hypertrophy; Ischemia; MicroRNAs; miRNA; multidisciplinary; Muscles; Myocardial infarction; Myocardium; Neonates; Overloading; Regeneration; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Transcription factors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-25211-4

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. Myocardial regeneration and proliferation of heart muscle cells is limited to a short period after birth early postnatal life, after which heart muscle cells can only grow in size and not in number. Here, the authors identified that the expression level of an endogenous microRNA cluster in heart muscle promotes the passage of the proliferative state to adult heart growth, and modulating the expression of this cluster can stimulate heart regeneration after myocardial infarction.