Ischemic heart disease is one of the main causes of morbidity and mortality in the world. In adult mammalian hearts, most cardiomyocytes are terminally differentiated and have extremely limited capacity of proliferation, making it impossible to regenerate the heart after injuries such as myocardial infarction. MicroRNAs (miRNAs), a class of non-coding single-stranded RNA, which are involved in mRNA silencing and the regulation of post-transcriptional gene expression, have been shown to play a crucial role in cardiac development and cardiomyocyte proliferation. Muscle specific miRNAs such as miR-1 are key regulators of cardiomyocyte maturation and growth, while miR-199-3p and other miRNAs display potent activity to induce proliferation of cardiomyocytes. Given their small size and relative pleiotropic effects, miRNAs have gained significant attraction as promising therapeutic targets or tools in cardiac regeneration. Increasing number of studies demonstrated that overexpression or inhibition of specific miRNAs could induce cardiomyocyte proliferation and cardiac regeneration. Some common targets of pro-proliferation miRNAs, such as the Hippo-Yap signaling pathway, were identified in multiple species, highlighting the power of miRNAs as probes to dissect core regulators of biological processes. A number of miRNAs have been shown to improve heart function after myocardial infarction in mice, and one trial in swine also demonstrated promising outcomes. However, technical difficulties, especially in delivery methods, and adverse effects, such as uncontrolled proliferation, remain. In this review, we summarize the recent progress in miRNA research in cardiac development and regeneration, examine the mechanisms of miRNA regulating cardiomyocyte proliferation, and discuss its potential as a new strategy for cardiac regeneration therapy.

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Myosin is a diverse superfamily of motor proteins responsible for actin-based motility and contractility in eukaryotic cells. Myosin-18 family, including myosin-18A and myosin-18B, belongs to an unconventional class of myosin, which lacks ATPase motor activity, and the investigations on their functions and molecular mechanisms in vertebrate development and diseases have just been initiated in recent years. Myosin-18A is ubiquitously expressed in mammalian cells, whereas myosin-18B shows strong enrichment in striated muscles. Myosin-18 family is important for cell motility, sarcomere formation, and mechanosensing, mostly by interacting with other cytoskeletal proteins and cellular apparatus. Myosin-18A participates in several intracellular transport processes, such as Golgi trafficking, and has multiple roles in focal adhesions, stress fibers, and lamellipodia formation. Myosin-18B, on the other hand, participates in actomyosin alignment and sarcomere assembly, thus relating to cell migration and muscle contractility. Mutations of either Myo18a or Myo18b cause cardiac developmental defects in mouse, emphasizing their crucial role in muscle development and cardiac diseases. In this review, we revisit the discovery history of myosin-18s and summarize the evolving understanding of the molecular functions of myosin-18A and myosin-18B, with an emphasis on their separate yet closely related functions in cell motility and contraction. Moreover, we discuss the diseases tightly associated with myosin-18s, especially cardiovascular defects and cancer, as well as highlight the unanswered questions and potential future research perspectives on myosin-18s.

Aims Postnatal maturation of mammalian cardiomyocytes proceeds rapidly after birth, with most of the myocytes exiting cell cycle, becoming binucleated, and adopting oxidative phosphorylation as the primary metabolic route. The triggers and transcriptional programs regulating cardiomyocyte maturation have not been fully understood yet. We performed single cell RNA-Seq in postnatal rat hearts in order to identify the important factors for this process. Methods and results Single cell RNA-Seq profiling was performed of postnatal day 1 and day 7 rat hearts, and we found that members of the AP-1 transcription factors showed a transient upregulation in the maturing cardiomyocytes, suggesting their functional involvement in the process. Activating members of the AP-1 family by palmitate or adrenergic stimulation inhibited cardiomyocyte cytokinesis and promoted cardiomyocyte maturation. In contrast, knocking down AP-1 members Atf3 and Jun promoted cardiomyocyte cytokinesis, reduced polyploidy and inhibited maturation. Mechanistically, RNA-Seq results and rescue experiments indicated that AP-1 members activate the expression of fatty acid metabolic genes to promote cardiomyocyte maturation. Finally, intraperitoneal injection of AP-1 inhibitor T-5224 in neonatal mice inhibits cardiomyocyte maturation in vivo. Conclusion Our results are the first evidence implicating AP-1 transcription factors in postnatal cardiomyocyte maturation both in vitro and in vivo, which expand our understanding of the molecular mechanism of cardiomyocyte maturation, and may lead to novel therapies to treat congenital heart diseases. Translational Perspective Postnatal cardiomyocyte maturation is a crucial process of cardiac development that determines fitness of the adult heart, and can be affected by multiple congenital heart diseases which lead to adult heart conditions. Our finding that AP-1 transcription factors transiently activated by multiple cues such as fatty acid and adrenergic signal promote cardiomyocyte maturation provided novel targets for therapeutic intervention, which may be applied during the narrow time window of postnatal cardiomyocyte maturation to treat congenital heart diseases and limit their impact on the adult heart.