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Extracellular vesicle (EV) miRNome profiling in hiPSC-cardiomyocyte differentiation reveals a stemness-maintenance miRNA cluster driving hiPSC-EV bioactivity

ABSTRACT: Extracellular Vesicles (EV) are an attractive therapy to boost cardiac regeneration. Nevertheless, identification of EV and corresponding cell platform(s) suitable for therapeutic application, is still a challenge. Here, we isolated EV from key stages of the human induced pluripotent stem cell-cardiomyocyte (hiPSC-CM) differentiation and maturation, i.e., from hiPSC (hiPSC-EV), cardiac progenitors (CPC-EV), immature (CMi-EV) and mature (CMm-EV) cardiomyocytes, with the aim of identifying a promising cell biofactory for EV production, and pinpoint the genetic signatures of bioactive EV. EV were characterized in terms of expression of specific markers, yield, and size. Bioactivity was assessed in human umbilical vein endothelial cells (HUVEC) and hiPSC-CM. Small RNA-Seq was performed to identify the differentially expressed miRNA in the four EV groups. Bioactivity assays showed increased tube formation and migration in HUVEC treated with hiPSC-EV compared to EV from committed cell populations. hiPSC-EV also significantly increased hiPSC-CM proliferation. Global miRNA expression profiles corroborated an EV-miRNA pattern indicative of stem cell to cardiomyocyte specification. A stemness maintenance miRNA cluster upregulated in hiPSC-EV was found to target the PTEN/PI3K/AKT pathway. Moreover, hiPSC-EV treatment mediated PTEN suppression and increased AKT phosphorylation. Overall, our findings validate hiPSC as suitable cell biofactories for EV production for cardiac regenerative applications.

ORGANISM(S): Homo sapiens

PROVIDER: GSE179323 | GEO | 2022/06/01

REPOSITORIES: GEO

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Extracellular vesicle (EV) miRNome profiling in hiPSC-cardiomyocyte differentiation reveals a stemness-maintenance miRNA cluster driving hiPSC-EV bioactivity

Project description:Extracellular vesicle (EV) miRNome profiling in hiPSC-cardiomyocyte differentiation reveals a stemness-maintenance miRNA cluster driving hiPSC-EV bioactivity

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Thyroid Hormone effects on hiPSC-derived cardiomyocytes (hiPSC-CM). Identification of target genes and pathways by RNA-Seq analysis

Project description:QT prolongation represents a dangerous and potentially life-threatening electrical event affecting the heart. Thyroid hormones (THs) are critical for cardiac development and heart function. However, little is known about THs influence on ventricular repolarization and controversial effects on QT prolongation are reported. Aim of this study was to characterize the direct effects of THs on the cardiac repolarization of human Induced Pluripotent Stem Cell derived cardiomyocytes (hiPSC-CM). RNA Seq analysis of hiPSC-CM treated with Thyroid Hormone T3 indicates significant deregulation in genes involved in cardiac pathways, in particular in ion homeostasis.

2021-12-08 | GSE172348 | GEO

Contractile work contributes to maturation of energy metabolism in hiPSC-derived cardiomyocytes

Project description:Energy metabolism is a key aspect of cardiomyocyte biology. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are a promising tool for biomedical application, but they are immature and have not undergone metabolic shift related to early postnatal development. Cultivation of hiPSC-CM in 3D engineered heart tissue (EHT) format leads to morphological maturation. This study compared the mitochondrial and metabolic state of hiPSC-CM in standard 2D culture and the EHT format and determined the influence of contractile activity. HiPSC-CM in EHTs showed ~2-fold higher number of mitochondria (electron microscopy), mitochondrial mass (mitotracker), DNA (Mt-ND1, Mt-ND2), and protein abundance (proteome) than in 2D culture. While hiPSC-CM exhibited the principal ability to use glucose, lactate and fatty acids as energy substrates irrespective of culture format, hiPSC-CM in 3D performed more oxidation of glucose, lactate and fatty acid, and less anaerobic glycolysis. The increase in mitochondrial mass and DNA in 3D was diminished by pharmacological inhibition of contractile force, suggesting that contractile work participates in mitochondrial development hiPSC-CM. In conclusion, contractile work in the EHT format contributes to metabolic maturation of hiPSC-CM.

2018-03-06 | PXD008205 | Pride

MYH7 G256E hiPSC-CM (Day 30)

Project description:MYH7 G256E hiPSC-CM (Day 30)

2024-04-15 | GSE220933 | GEO

MPC EV miRNA Microarray

Project description:MPC EV miRNA Microarray

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Maturation of hiPSC-derived cardiomyocytes in tri-cellular cardiac microtissues promotes adult alternative splicing of SCN5A revealing effects of mutations in cardiac disease

Project description:Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are used to examine in vitro the effect of mutations in the cardiac sodium channel gene SCN5A, associated with cardiac arrhythmias. Postnatally SCN5A undergoes a fetal-to-adult isoform switch, but hiPSC-CMs in conventional 2-dimensional cultures are fetal-like. This impedes evaluation of mutations in the adult isoform. Here, we derived hiPSC-CMs from a patient carrying compound mutations in the adult SCN5A exon 6B and in exon 4 and generated isogenic corrected lines. In hiPSC-CM 2-dimensional culture, exon 6B mutation did not affect single-cell electrophysiology because of its limited expression. CRISPR/Cas9-mediated excision of the fetal exon 6A with did not promote adult SCN5A expression, rather it impaired the splicing. By maturing hiPSC-CMs in three-dimensional tri-cell type cardiac microtissues, SCN5A underwent isoform switch and revealed the functional effect of exon 6B mutation. Upregulation of the splicing factor MBNL1 in hiPSC-CMs either by culture in microtissues or by overexpression was sufficient to promote exon 6B inclusion. Our results support the ability to study developmentally regulated cardiac genes and postnatal cardiac arrhythmias using hiPSC cardiac cells.

2023-05-03 | GSE180290 | GEO

Secretome containing extracellular vesicles (EV) from cardiovascular progenitors (EV-CPC) vs the secretome containing EV from Fibroblasts (EV-FB)

Project description:Secretome containing extracellular vesicles (EV) seem to mediate the benefits of cell therapy for ischemic heart failure. Our project has the objective of comparing the secretome containing extracellular vesicles (EV) from cardiac progenitor cells (EV-CPC) vs the secretome containing EV from Fibroblasts (EV-FB) in order to stablish a protein cartography of EV-CPC and the biological pathways that they are involved. seem to mediate the benefits of cell therapy for ischemic heart failure. Our project has the objective of comparing the secretome containing extracellular vesicles (EV) from cardiac progenitor cells (EV-CPC) vs the secretome containing EV from Fibroblasts (EV-FB) in order to stablish a protein cartography of EV-CPC and the biological pathways that they are involved.

2023-09-22 | PXD022129 | Pride

RNA Expression Profiling of Human iPSC-Derived Cardiomyocytes in a Cardiac Hypertrophy Model [mRNA expression]

Project description: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. We utilized a previously established in vitro model of cardiac hypertrophy to interrogate the regulatory mechanism associated with the cardiac disease process. We performed 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-1stimulated 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. To characterize miRNA and mRNA expression patterns we utilized iCell Cardiomyocytes derived from human iPSCs (hiPSC-CMs). Based on preliminary dose-response and time-course studies, we stimulated these cells with ET-1 at 10-8M for 18h. We used unstimulated control (control-CM) and ET-1 stimulated (ET1-CM) hiPSCs from 3 separate experiments as triplicate data for this study. mRNA expression for the control-CM and ET1-CM samples was analyzed using GeneChip 3M-bM-^@M-^YIVT express arrays (Affymetrix).

2014-10-03 | E-GEOD-60291 | biostudies-arrayexpress

miRNA expression profiling of differentiating human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes

Project description:To gain insight into the molecular regulation of human heart development, a detailed comparison of the mRNA and miRNA transcriptomes across differentiating human-induced pluripotent stem cell (hiPSC)–derived cardiomyocytes and biopsies from fetal, adult, and hypertensive human hearts was performed. Gene ontology analysis of the mRNA expression levels of the hiPSCs differentiating into cardiomyocytes revealed 3 distinct groups of genes: pluripotent specific, transitional cardiac specification, and mature cardiomyocyte specific. Hierarchical clustering of the mRNA data revealed that the transcriptome of hiPSC cardiomyocytes largely stabilizes 20 days after initiation of differentiation. Nevertheless, analysis of cells continuously cultured for 120 days indicated that the cardiomyocytes continued to mature toward a more adult-like gene expression pattern. Analysis of cardiomyocyte-specific miRNAs (miR-1, miR-133a/b, and miR-208a/b) revealed a miRNA pattern indicative of stem cell to cardiomyocyte specification. A biostatistitical approach integrated the miRNA and mRNA expression profiles revealing a cardiomyocyte differentiation miRNA network and identified putative mRNAs targeted by multiple miRNAs. Together, these data reveal the miRNA network in human heart development and support the notion that overlapping miRNA networks re-enforce transcriptional control during developmental specification. miRNA expression profiling of differentiating human-induced pluripotent stem cell (hiPSC)–derived cardiomyocytes (days 0-120)

2012-02-10 | E-GEOD-35672 | biostudies-arrayexpress

Geometry-dependent functional changes in iPSC-derived cardiomyocytes

Project description:Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are a promising platform for cardiac studies in vitro, and possibly for tissue repair in humans. However, hiPSC-CM cells tend to retain morphology, metabolism, patterns of gene expression, and electrophysiology similar to that of embryonic cardiomyocytes. We grew hiPSC-CM in patterned islands of different sizes and shapes, and measured the effect of island geometry on action potential waveform and calcium dynamics using optical recordings of voltage and calcium from 970 islands of different sizes. hiPSC-CM in larger islands showed electrical and calcium dynamics indicative of greater functional maturity. We then compared transcriptional signatures of the small and large islands against a developmental time course of cardiac differentiation. Although island size had little effect on expression of most genes whose levels differed between hiPSC-CM and adult primary CM, we identified a subset of genes for which island size drove the majority (58%) of the changes associated with functional maturation. Finally, we patterned hiPSC-CM on islands with a variety of shapes to probe the relative contributions of soluble factors, electrical coupling, and direct cell-cell contacts to the functional maturation. Collectively, our data show that optical electrophysiology is a powerful tool for assaying hiPSC-CM maturation, and that island size powerfully drives activation of a subset of genes involved in cardiac maturation.

2017-06-06 | GSE95296 | GEO

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