miRNA in cardiac development and regeneration

Zhaohui Ouyang, Ke Wei

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.