Abstract
Cardiovascular disease is still the leading cause of morbidity and mortality worldwide. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have become a valuable widespread in vitro model to study cardiac disease. Herein, we employ the hiPSC-CM model to identify novel miRNA–mRNA interaction partners during cardiac differentiation and β-adrenergic stress. Whole transcriptome and small RNA sequencing data were combined to identify novel miRNA–mRNA interactions. Briefly, mRNA and miRNA expression profiles were integrated with miRNA target predictions to identify significant statistical dependencies between a miRNA and its candidate target set. We show by experimental validation that our approach discriminates true from false miRNA target predictions. Thereby, we identified several differentially expressed miRNAs and focused on the two top candidates: miR-99a-5p in the context of cardiac differentiation and miR-212-3p in the context of β-adrenergic stress. We validated some target mRNA candidates by 3′UTR luciferase assays as well as in transfection experiments in the hiPSC-CM model system. Our data show that iPSC-derived cardiomyocytes and computational modeling can be used to uncover new valid miRNA–mRNA interactions beyond current knowledge.
Highlights
Cardiovascular diseases (CVDs) are a major cause of disease burden in the world, with incidence rates on the rise [1]
We characterized the gene expression changes observed during cardiomyocyte differentiation from Human Induced Pluripotent Stem Cell (hiPSC) and confirmed their suitability for the analysis of molecular events regarding cardiac lineage development, fetal gene program activation, as well as cardiac response to stimuli [21]
We identified important expression changes in miRNA and mRNA expression levels at different stages of cardiac lineage development
Summary
Cardiovascular diseases (CVDs) are a major cause of disease burden in the world, with incidence rates on the rise [1]. Most therapy options focus on treating symptoms and improving quality of life rather than curing the disease. This is largely due to a lack of understanding of the molecular mechanisms underlying CVDs. Hypertrophic growth of cardiomyocytes is a compensatory mechanism to normalize heart performance during myocardial stress. Prolonged mechanical load on the heart can lead to progression towards pathological hypertrophy [2]. Pathological cardiac hypertrophy is a maladaptive process accompanying various forms of CVD, such as prolonged hypertension, valvular heart disease, and heart failure. Elucidating the molecular components and pathways that orchestrate the progression from pathological hypertrophy to heart failure is the focus of a lot of studies in the field of cardiology. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have become valuable tools to study important regulators of cardiac function and the molecular pathways underlying cardiac pathologies [3,4]
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