This study states that Adult mammalian hearts cannot regenerate after myocardial infarction (MI): cardiomyocytes (CMs) that die after MI are replaced with a fibrotic scar that compromises heart function and induces heart failure. Gene delivery through modified mRNA (modRNA) is a safe, transient, nonimmunogenic, local, controlled platform that rapidly translates genes in heart cells after MI.1 We recently demonstrated that our specific modRNA translation system (SMRTs) delivers potent intracellular genes (eg, cell cycle–promoting Pkm2 [pyruvate kinase muscle isoenzyme 2]), which are beneficial when expressed in 1 cell type (CM), but not others (non-CM), exclusively to CMs.2 Here we show how SMRTs allows modRNA translation only in CMs or non-CMs both in culture and after MI. SMRTs may reduce several CM-specific microRNAs (cmsmiRs) that are detrimental after MI. miR208a encodes using the same intron as the CM-specific marker Myh6 and induces hypertrophy by upregulating β-myosin heavy chain.3 Elevated muscle-specific miR-1 increases cell death.4 CM-specific miR-199a impairs autophagy and promotes cardiac hypertrophy through mTOR [mammalian target of rapamycin] activation.5 We created 4 inactive human CD25 (reporter gene ihCD25) modRNAs with or without recognition elements for these cardiac-detrimental cmsmiRs. We transfected these modRNAs into neonatal rat heart cells and immunostained them for hCD25 1 day later in vitro. 

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