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Signature of circular RNAs in human induced pluripotent stem cells and derived cardiomyocytes.

ABSTRACT: BACKGROUND:Circular RNAs (circRNAs) are regarded as a novel class of noncoding RNA regulators. Although a number of circRNAs have been identified by bioinformatics analysis of RNA-seq data, tissue and disease-specific circRNAs are still to be uncovered to promote their application in basic research and clinical practice. The purpose of this study was to explore the circRNA profiles in human induced pluripotent stem cells (hiPSCs) and hiPSC-derived cardiomyocytes (hiPSC-CMs), and to identify cardiac or disease-specific circRNAs. METHODS:hiPSCs were generated from fibroblasts, and then further differentiated to hiPSC-CMs by modulating WNT signaling in RPMI+B27 medium. Following high-throughput RNA sequencing, circRNAs were extracted and quantified by a combined strategy known as CIRCexplorer. Integrative analysis was performed to illuminate the correlation between circRNAs and their parental linear isoforms. Cardiac and disease-specific expression of circRNAs was confirmed by quantitative reverse-transcription PCR. RESULTS:In this study, a total of 5602 circRNAs were identified in hiPSCs and hiPSC-CMs. Our data indicated, for the first time, more enriched expression of circRNAs in differentiated cardiomyocytes than in undifferentiated hiPSCs. In addition to the host gene-dependent expression, our integrative analysis also identified a number of circRNAs showing host gene-independent expression in hiPSCs and hiPSC-CMs. CircRNAs including circSLC8A1, circCACNA1D, circSPHKAP and circALPK2 showed cardiac-selective expression during cardiac differentiation and human heart-specific enrichment in fetal tissues. Furthermore, circSLC8A1 abnormally increased in heart tissues from patients suffering from dilated cardiomyopathy. CONCLUSIONS:CircRNAs are highly enriched in hiPSC-differentiated CMs, and cardiac-specific circRNAs such as circSLC8A1, circCACNA1D, circSPHKAP and circALPK2 may serve as biomarkers of CMs. Detection of the excessive expression of circSLC8A1 provides a potential approach for pathological status indication of heart disease.

SUBMITTER: Lei W

PROVIDER: S-EPMC5845222 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Signature of circular RNAs in human induced pluripotent stem cells and derived cardiomyocytes.

Lei Wei W Feng Tingting T Fang Xing X Yu You Y Yang Junjie J Zhao Zhen-Ao ZA Liu Junwei J Shen Zhenya Z Deng Wenbo W Hu Shijun S

Stem cell research & therapy 20180309 1

<h4>Background</h4>Circular RNAs (circRNAs) are regarded as a novel class of noncoding RNA regulators. Although a number of circRNAs have been identified by bioinformatics analysis of RNA-seq data, tissue and disease-specific circRNAs are still to be uncovered to promote their application in basic research and clinical practice. The purpose of this study was to explore the circRNA profiles in human induced pluripotent stem cells (hiPSCs) and hiPSC-derived cardiomyocytes (hiPSC-CMs), and to ident ...[more]

PMID: 29523209

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Project description:Hundreds of thousands of people die each year as a result of sudden cardiac death, and many are due to heart rhythm disorders. One of the major causes of these arrhythmic events is Brugada syndrome, a cardiac channelopathy that results in abnormal cardiac conduction, severe life-threatening arrhythmias, and, on many occasions, death. This disorder has been associated with mutations and dysfunction of about two dozen genes; however, the majority of the patients do not have a definite cause for the diagnosis of Brugada Syndrome. The protein-coding genes represent only a very small fraction of the mammalian genome, and the majority of the noncoding regions of the genome are actively transcribed. Studies have shown that most of the loci associated with electrophysiological traits are located in noncoding regulatory regions and are expected to affect gene expression dosage and cardiac ion channel function. Noncoding RNAs serve an expanding number of regulatory and other functional roles within the cells, including but not limited to transcriptional, post-transcriptional, and epigenetic regulation. The major noncoding RNAs found in Brugada Syndrome include microRNAs; however, others such as long noncoding RNAs are also identified. They contribute to pathogenesis by interacting with ion channels and/or are detectable as clinical biomarkers. Stem cells have received significant attention in the recent past, and can be differentiated into many different cell types including those in the heart. In addition to contractile and relaxational properties, BrS-relevant electrophysiological phenotypes are also demonstrated in cardiomyocytes differentiated from stem cells induced from adult human cells. In this review, we discuss the current understanding of noncoding regions of the genome and their RNA biology in Brugada Syndrome. We also delve into the role of stem cells, especially human induced pluripotent stem cell-derived cardiac differentiated cells, in the investigation of Brugada syndrome in preclinical and clinical studies.

Project description:RationaleCardiomyocytes generated from human induced pluripotent stem cells (hiPSCs) are suggested as the most promising candidate to replenish cardiomyocyte loss in regenerative medicine. Little is known about their calcium homeostasis, the key process underlying excitation-contraction coupling.ObjectiveWe investigated the calcium handling properties of hiPSC-derived cardiomyocytes and compared with those from human embryonic stem cells (hESCs).Methods and resultsWe differentiated cardiomyocytes from hiPSCs (IMR90 and KS1) and hESCs (H7 and HES3) with established protocols. Beating outgrowths from embryoid bodies were typically observed 2 weeks after induction. Cells in these outgrowths were stained positively for tropomyosin and sarcomeric alpha-actinin. Reverse-transcription polymerase chain reaction studies demonstrated the expressions of cardiac-specific markers in both hiPSC- and hESC-derived cardiomyocytes. Calcium handling properties of 20-day-old hiPSC- and hESC-derived cardiomyocytes were investigated using fluorescence confocal microscopy. Compared with hESC-derived cardiomyocytes, spontaneous calcium transients from both lines of hiPSC-derived cardiomyocytes were of significantly smaller amplitude and with slower maximal upstroke velocity. Better caffeine-induced calcium handling kinetics in hESC-CMs indicates a higher sacroplasmic recticulum calcium store. Furthermore, in contrast with hESC-derived cardiomyocytes, ryanodine did not reduce the amplitudes, maximal upstroke and decay velocity of calcium transients of hiPSC-derived cardiomyocytes. In addition, spatial inhomogeneity in temporal properties of calcium transients across the width of cardiomyocytes was more pronounced in hiPSC-derived cardiomyocytes than their hESC counterpart as revealed line-scan calcium imaging. Expressions of the key calcium-handling proteins including ryanodine recptor-2 (RyR2), sacroplasmic recticulum calcium-ATPase (SERCA), junction (Jun) and triadin (TRDN), were significantly lower in hiPSC than in hESCs.ConclusionsThe results indicate the calcium handling properties of hiPSC-derived cardiomyocytes are relatively immature to hESC counterparts.

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Signature of circular RNAs in human induced pluripotent stem cells and derived cardiomyocytes.

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Signature of circular RNAs in human induced pluripotent stem cells and derived cardiomyocytes.

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