RNA Expression Profiling of Human iPSC-Derived Cardiomyocytes in a Cardiac Hypertrophy Model

Abstract

Cardiac hypertrophy is an independent risk factor for cardiovascular disease and heart failure. There is increasing evidence that microRNAs (miRNAs) play an important role in the regulation of messenger RNA (mRNA) and the pathogenesis of various cardiovascular diseases. However, the ability to comprehensively study cardiac hypertrophy on a gene regulatory level is impacted by the limited availability of human cardiomyocytes. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer the opportunity for disease modeling. Here we utilize a previously established in vitro model of cardiac hypertrophy to interrogate the regulatory mechanism associated with the cardiac disease process. We perform miRNA sequencing and mRNA expression analysis on endothelin 1 (ET-1) stimulated hiPSC-CMs to describe associated RNA expression profiles. MicroRNA sequencing revealed over 250 known and 34 predicted novel miRNAs to be differentially expressed between ET-1 stimulated and unstimulated control hiPSC-CMs. Messenger RNA expression analysis identified 731 probe sets with significant differential expression. Computational target prediction on significant differentially expressed miRNAs and mRNAs identified nearly 2000 target pairs. A principal component analysis approach comparing the in vitro data with human myocardial biopsies detected overlapping expression changes between the in vitro samples and myocardial biopsies with Left Ventricular Hypertrophy. These results provide further insights into the complex RNA regulatory mechanism associated with cardiac hypertrophy.

MiR‐590 Promotes Transdifferentiation of Porcine and Human Fibroblasts Toward a Cardiomyocyte‐Like Fate by Directly Repressing Specificity Protein 1

“…The miR‐590 family, more specifically, which is comprised of 2 miRNAs—miR‐590‐5p and miR‐590‐3p—is thought to play a key role in cardiovascular disease through its protection of blood vessels, regulation of lipid metabolism, and prevention of myocarditis and atherosclerosis through its target genes . miR‐590 is expressed in human induced pluripotent stem‐cell‐derived cardiomyocytes and in the human heart . miR‐590 regulates signaling pathways (TGF‐β, protein kinase B) involved in cardiac fibrosis/remodeling, embryonic stem cell proliferation/cardiac differentiation, and metabolism by suppressing TGF‐β receptor II .…”

Translation of Human-Induced Pluripotent Stem Cells

“…For example, iPSC-CMs are being used in cell-based assays to model susceptibility to drug-induced cardiotoxicity (75,76), thereby allowing researchers to predict adverse drug responses more accurately in patients with different genetic backgrounds. Similarly, iPSC-CMs have been used to understand the disease progression of diabetic cardiomyopathy (77), viral myocarditis (78), cardiac hypertrophy (79), and genetic polymorphism-induced cardiac ischemia (80). …”

Human Induced Pluripotent Stem Cells as a Platform for Personalized and Precision Cardiovascular Medicine

“…In a separate study, microRNA (miRNA) sequencing showed that ET-1 treatment in hiPSC-CMs leads to differential expression of 250 known (e.g., miR-23a-3p and miR208a-3p) and 34 novel miRNAs, the majority of which were associated with corresponding mRNA expression changes (2). Some of the complex RNA regulatory mechanisms associated with cardiac hypertrophy were involved in cardiovascular development (e.g., MEF2C), cell proliferation and transformation (e.g., MYC, FOS, TGFB2, and TGFBR3), and mitogen-activated protein kinase signal transduction (e.g., MAP3K9 and MAP2K6).…”