Dynamic changes of mRNA expression during development of human embryonic stem cells derived cardiomyocytes
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE239918 | GEO | 2023/08/07
REPOSITORIES: GEO
Similar Datasets
Project description:Cardiovascular disease is a leading cause of death worldwide. Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) hold immense clinical potential and recent studies have enabled generation of virtually pure hPSC-CMs with high efficiency in chemically defined and xeno-free conditions. Despite these advances, hPSC-CMs exhibit an immature phenotype and are arrhythmogenic in vivo, necessitating development of methods to mature these cells. hPSC-CMs undergo significant metabolic alterations during differentiation and maturation. A detailed analysis of the metabolic changes accompanying maturation of hPSC-CMs may prove useful in identifying new strategies to expedite the maturation process and also provide biomarkers for testing or validating hPSC-CM maturation. In this study we identified global metabolic changes which take place during long-term culture and maturation of hPSC-CMs derived from three different hPSC lines. We have identified several metabolic pathways, including phospholipid metabolism and pantothenate and Coenzyme A metabolism, which showed significant enrichment upon maturation in addition to fatty acid oxidation and metabolism. We also identified an increase in glycerophosphocholine and reduction in phosphocholine as potential metabolic biomarkers of maturation. These biomarkers were also affected in a similar manner during murine heart development in vivo. These results support that hPSC-CM maturation is associated with extensive metabolic rewiring and understanding the role of these metabolic changes in maturation process has the potential to develop novel approaches to monitor and expedite hPSC-CM maturation.
2018-04-24 | MTBLS425 | MetaboLights
Project description:Decades of progress in developmental cardiology has advanced our understanding of the early aspects of heart development, including cardiomyocyte (CM) differentiation. However, control of CM maturation which is subsequently required to generate adult myocytes, remains elusive. Here, we analyzed over 200 microarray datasets from early embryonic to adult hearts and identified a large number of genes whose expression shifts gradually and continuously during maturation. We generated an atlas of integrated gene expression, biological pathways, transcriptional regulators, and gene regulatory networks (GRNs), which show discrete sets of key transcriptional regulators and pathways activated or suppressed during CM maturation. We developed a GRN-based program named MatStatCM that indexes CM maturation status. MatStatCM reveals that pluripotent stem cell-derived CMs mature early in culture, but are arrested at the late embryonic stage with aberrant regulation of key transcription factors. Our study provides a foundation for understanding CM maturation.
2015-11-16 | GSE73233 | GEO
Project description:Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide great opportunities for mechanistic dissection of human cardiac pathophysiology; however, hiPSC-CMs remain immature relative to the adult heart. To identify novel signaling pathways driving the maturation process during heart development, we analyzed published transcriptional and epigenetic datasets from hiPSC-CMs, prenatal and postnatal human hearts. These analyses revealed that several components of the MAPK and PI3K-AKT pathways are downregulated in the postnatal heart. Here, we show that dual inhibition of these pathways for only 5 days significantly enhances the maturation of day-30 hiPSC-CMs in many domains: hypertrophy, multinucleation, metabolism, t-tubule density, calcium handling, and electrophysiology, many equivalent to day-60 hiPSC-CMs. These data indicate that the MAPK/PI3K/AKT pathways are involved in cardiomyocyte maturation and provide proof-of-concept for the manipulation of key signaling pathways for optimal hiPSC-CM maturation, a critical aspect of faithful in vitro modeling of cardiac pathologies and subsequent drug discovery.
2022-08-04 | GSE187308 | GEO
Project description:We report the application of bioChIP-seq, bulk RNA-seq, Hi-C, H3K27ac HiChIP, and Massively parallel reporter assays (MPRAs) to characterize the p300-bound regulatory regions in murine cardiomyocytes (CMs). By obtaining ChIP-seq data of coactivator p300 from seven developmental stages of mouse CMs, we defined the dynamic p300 enhancers from embryonic CMs to adult CMs. We then validated the activity of dynamic p300 enhancers with AAV9-based MPRAs, we found dynamic p300 enhancers show dynamic activity from postnatal day 0 (P0) CMs to 4-week-old CMs. In addition, MRPA results suggest nuclear receptor motifs are required for the activity of some p300 late enhancers. With Hi-C and H3K27ac HiChIP data of E12.5, P0 and adult CMs, we identified chromatin structure changes such as chromatin loops, compartment switch, and new TAD boundaries are associated with dynamic p300 binding. This study provides data source of CM-selective p300 enhancers, chromatin 3D structure and gene expression during CM development and maturation.
2023-01-19 | GSE222160 | GEO
Project description:We report the application of bioChIP-seq, bulk RNA-seq, Hi-C, and Massively parallel reporter assays (MPRAs) to characterize the p300-bound regulatory regions in murine cardiomyocytes (CMs). By obtaining ChIP-seq data of coactivator p300 from seven developmental stages of mouse CMs, we defined the dynamic p300 enhancers from embryonic CMs to adult CMs. We then validated the activity of dynamic p300 enhancers with AAV9-based MPRAs, we found dynamic p300 enhancers show dynamic activity from postnatal day 0 (P0) CMs to 4-week-old CMs. In addition, MRPA results suggest nuclear receptor motifs are required for the activity of some p300 late enhancers. With Hi-C data of E12.5, P0 and adult CMs, we identified chromatin structure changes such as chromatin loops, compartment switch, and new TAD boundaries are associated with dynamic p300 binding. This study provides data source of CM-selective p300 enhancers, chromatin 3D structure and gene expression during CM development and maturation.
2023-01-19 | GSE195902 | GEO
Project description:We report the application of bioChIP-seq, bulk RNA-seq, Hi-C, and Massively parallel reporter assays (MPRAs) to characterize the p300-bound regulatory regions in murine cardiomyocytes (CMs). By obtaining ChIP-seq data of coactivator p300 from seven developmental stages of mouse CMs, we defined the dynamic p300 enhancers from embryonic CMs to adult CMs. We then validated the activity of dynamic p300 enhancers with AAV9-based MPRAs, we found dynamic p300 enhancers show dynamic activity from postnatal day 0 (P0) CMs to 4-week-old CMs. In addition, MRPA results suggest nuclear receptor motifs are required for the activity of some p300 late enhancers. With Hi-C data of E12.5, P0 and adult CMs, we identified chromatin structure changes such as chromatin loops, compartment switch, and new TAD boundaries are associated with dynamic p300 binding. This study provides data source of CM-selective p300 enhancers, chromatin 3D structure and gene expression during CM development and maturation.
2023-01-19 | GSE195901 | GEO
Project description:We report the application of bioChIP-seq, bulk RNA-seq, Hi-C, and Massively parallel reporter assays (MPRAs) to characterize the p300-bound regulatory regions in murine cardiomyocytes (CMs). By obtaining ChIP-seq data of coactivator p300 from seven developmental stages of mouse CMs, we defined the dynamic p300 enhancers from embryonic CMs to adult CMs. We then validated the activity of dynamic p300 enhancers with AAV9-based MPRAs, we found dynamic p300 enhancers show dynamic activity from postnatal day 0 (P0) CMs to 4-week-old CMs. In addition, MRPA results suggest nuclear receptor motifs are required for the activity of some p300 late enhancers. With Hi-C data of E12.5, P0 and adult CMs, we identified chromatin structure changes such as chromatin loops, compartment switch, and new TAD boundaries are associated with dynamic p300 binding. This study provides data source of CM-selective p300 enhancers, chromatin 3D structure and gene expression during CM development and maturation.
2023-01-19 | GSE194087 | GEO
Project description:Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have wide potential application in basic research, drug discovery, and regenerative medicine, but functional maturation remains challenging. Here, we present a simple method whereby maturation of hiPSC-CMs can be accelerated by simultaneous application of physiological Ca 2+ and frequency-ramped electrical pacing in culture. This combination produces realistic force-frequency relationship, physiological twitch kinetics, robust β-adrenergic response, improved Ca 2+ handling, and cardiac troponin I expression within 25 days. This study provides insights into the role of Ca 2+ in hiPSC-CM maturation and offers a scalable platform for translational and clinical research.
2022-04-28 | GSE201437 | GEO
Project description:Contrary to adult mammals, zebrafish are able to regenerate their heart after cardiac injury. This regenerative response relies, in part, on the endogenous ability of cardiomyocytes (CMs) to dedifferentiate and proliferate to replenish the lost muscle. However, CM heterogeneity and population dynamics during development and regeneration remain poorly understood. Through comparative transcriptomic analyses of the developing and adult zebrafish heart, we identified tnnc2 and tnni4b.3 expression as markers for CMs at early and late developmental stages, respectively. Using newly developed reporter lines for these genes, we investigated their expression dynamics during development and regeneration, and observed interesting expression patterns. tnnc2 reporter lines label most CMs at embryonic stages, and this labeling declines rapidly during larval stages; in adult hearts expression is only detectable in a subset of CMs. Conversely, expression of a tnni4b.3 reporter is initially visible in outer curvature CMs at larval stages, and it is subsequently present in a vast majority of the CMs in adult hearts. Interestingly, we find that the adult CMs labeled by the embryonic reporter display higher levels of Tg(tp1:EGFP) expression, which indicates active Notch signaling. To further characterize this CM population, we performed transcriptomic analysis and found that it expresses genes encoding components of the Notch signaling pathway as well as markers of immature CMs. Moreover, during heart regeneration, proliferating CMs in the injured area activate the embryonic CM reporter. Overall, our findings provide further evidence of cardiomyocyte heterogeneity in the adult zebrafish heart.
2021-05-03 | GSE157662 | GEO
Project description:Rationale: Human pluripotent stem cells-derived cardiomyocytes (hPSC-CMs) exhibit the properties of fetal CMs, which limit their applications. Various methods have been used to promote maturation of hPSC-CMs; however, there is a lack of an unbiased and comprehensive method for accurate benchmarking of hPSC-CM maturation.
Objective: We aim to develop an unbiased proteomics method integrating high-throughput top-down targeted proteomics and bottom-up global proteomics for accurate and comprehensive assessment of hPSC-CM maturation.
Methods and Results: Utilizing hPSC-CMs from early- and late-stage two-dimensional monolayer culture and three-dimensional engineered cardiac tissue, we demonstrated high reproducibility and reliability of the top-down proteomics method, which enabled simultaneous quantification of contractile protein isoform expressions and their PTMs. This method allowed for the detection of known maturation-associated contractile protein alterations, and for the first time, identified contractile protein PTMs as promising new markers of maturation. By employing a global proteomics strategy, we identified candidate maturation markers important for sarcomere organization, cardiac excitability, and Ca2+ homeostasis; and validated these markers in the developing mouse cardiac ventricles.
Conclusions: We established an unbiased proteomics method that can provide accurate and specific benchmarking of hPSC-CM maturation, and identified new markers of maturation. Furthermore, this integrated proteomics strategy laid a strong foundation for uncovering molecular basis underlying cardiac development and disease using hPSC-CMs.
| MSV000082985 | MassIVE