Targeting miRNAs to Induce a Cardiac Phenotype in Pluripotent Stem Cells

Stimulation of cardiomyocyte lineage commitment was reported in embryonic stem cells (ESCs) and inducible pluripotent stem cells (iPSCs) as a potential strategy to promote cardiac regeneration. Human ESC-derived cardiomyocytes enhanced cardiac function in a rat myocardial infarction model (Laflamme et al. 2007). In addition, integration and survival of human ESC-derived cardiomyocytes after transplantation in nonhuman primates in an experimental myocardial infarct model were reported recently. Re-muscularization of substantial amounts of the infarcted monkey heart was observed, albeit with occurrence of nonfatal ventricular arrhythmias (Chong et al. 2014). Dynamic regulation of miRNA is involved in differentiation of ESCs toward a cardiomyocyte fate. In vitro, induction of miR-1 and miR-499 in the differentiation from human ECS and cardiac progenitor cells toward cardiomyocytes was observed. Forced expression of these miRNAs enhanced differentiation toward a cardiomyocyte fate (Wilson et al. 2010; Sluijter et al. 2010). In vivo, transplantation of hESCs treated with miR-1 mimics improved cardiac function and increased the number of donor-derived cardiomyocytes (Glass and Singla 2011). Of interest, cardiac apoptosis was decreased after treatment (Glass and Singla 2011) suggesting that miR-1 not only facilitates cardiomyocyte differentiation but also contributes to cardioprotection after cardiac injury via paracrine mechanisms. Using miRNA sequencing and bioinformatical analysis in hESCs-derived cardiomyocytes before and after (1 year) cardiac maturation revealed a pronounced upregulation of members of the let-7 family. Overexpression of let-7 in human ESC-CMs accelerated cardiac maturation as shown by enhanced morphological and functional characteristics. Profiling after overexpression of let-7 members showed upregulation of fatty acid metabolism and downregulation of PI3/AKT/insulin signaling, suggesting that a metabolic switch enhances cardiomyocyte maturation (Kuppusamy et al. 2015). Together, these studies reveal important roles of miRNAs for cardiac lineage commitment and maturation of pluripotent stem cells.

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