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 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 derepressing the prohypertrophic transcription factors Hand2 and Mef2d. Viral gene delivery of miR-106b∼25 provokes nearly complete regeneration of the adult myocardium after ischemic injury.
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Raso A, Dirkx E, Sampaio-Pinto V, El Azzouzi H, Cubero RJ, Sorensen DW, Ottaviani L, Olieslagers S, Huibers MM, de Weger R, Siddiqi S, Moimas S, Torrini C, Zentillin L, Braga L, Nascimento DS, da Costa Martins PA, van Berlo JH, Zacchigna S, Giacca M, De Windt LJ. A microRNA program regulates the balance between cardiomyocyte hyperplasia and hypertrophy and stimulates cardiac regeneration. Nat Commun. 2021 [doi: 10.1038/s41467-021-25211-4] [PubMed]