PPARdelta signaling activation improves metabolic and contractile maturation of human pluripotent stem cell-derived cardiomyocytes
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ABSTRACT:
PROVIDER: PRJNA741792 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14924736_1.fastq.gz | Fastqsanger.gz | |||
| SRR14924736_2.fastq.gz | Fastqsanger.gz | |||
| SRR14924737_1.fastq.gz | Fastqsanger.gz | |||
| SRR14924737_2.fastq.gz | Fastqsanger.gz | |||
| SRR14924738_1.fastq.gz | Fastqsanger.gz |
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Project description:Pluripotent stem cell-derived cardiomyocytes (PSC-CMs) provide an unprecedented opportunity to study human heart development and disease. A major caveat however is that they remain functionally and structurally immature in culture, limiting their potential for disease modeling and regenerative approaches. Here we address the question of how different metabolic pathways can be modulated in order to induce efficient cardiac maturation of hPSC-CMs. We show that PPAR signaling acts in an isoform-specific manner to balance the glycolysis and fatty acid oxidation (FAO) pathways. PPARd activation or inhibition results in efficient respective up- or down-regulation of the gene regulatory networks underlying FAO in hPSC-CMs. PPARd induction further increases mitochondrial and peroxisome content, enhances mitochondrial cristae formation and augments FAO flux. Lastly PPARd activation results in enhanced myofibril organization and increased numbers of bi-nucleated hPSC-CMs. Transient lactate exposure, commonly used in hPSC-CM purification protocols, induces an independent program of cardiac maturation, but when combined with PPARd activation equally results in a metabolic switch to FAO. In summary, we identify multiple axes of metabolic modifications of hPSC-CMs including a role for PPARdelta signaling in inducing the metabolic switch to FAO in hPSC-CMs. Our findings provide new opportunities to generate and use metabolically mature hPSC-CMs including for disease modeling and regenerative therapy.
2022-04-09 | GSE178984 | GEO
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
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
Project description:PPARdelta signaling induces metabolic maturation in human pluripotent stem cell-derived cardiomyocytes
| PRJNA675079 | ENA
Project description:Metabolic Maturation Media Improves Physiological Function of Human iPSC-derived Cardiomyocytes
| PRJNA635378 | ENA
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:Pluripotent stem cell-derived cardiomyocytes (PSC-CMs) provide an unprecedented opportunity to study human heart development and disease. A major caveat however is that they remain functionally and structurally immature in culture, limiting their potential for disease modeling and regenerative approaches. Here we address the question of how different metabolic pathways can be modulated in order to induce efficient cardiac maturation of hPSC-CMs. We show that PPAR signaling acts in an isoform-specific manner to balance the glycolysis and fatty acid oxidation (FAO) pathways. PPARd activation or inhibition results in efficient respective up- or down-regulation of the gene regulatory networks underlying FAO in hPSC-CMs. PPARd induction further increases mitochondrial and peroxisome content, enhances mitochondrial cristae formation and augments FAO flux. Lastly PPARd activation results in enhanced myofibril organization and increased numbers of bi-nucleated hPSC-CMs. Transient lactate exposure, commonly used in hPSC-CM purification protocols, induces an independent program of cardiac maturation, but when combined with PPARd activation equally results in a metabolic switch to FAO. In summary, we identify multiple axes of metabolic modifications of hPSC-CMs including a role for PPARdelta signaling in inducing the metabolic switch to FAO in hPSC-CMs. Our findings provide new opportunities to generate and use metabolically mature hPSC-CMs including for disease modeling and regenerative therapy.
2021-11-01 | GSE160987 | GEO
Project description:Akt is a serine/threonine protein kinase that is activated by a variety of growth factors or cytokines in a PI3-kinase dependent manner. Using a conditional transgenic system in which Akt signaling can be turned on or off in the adult heart, we have recently demonstrated that short-term Akt activation induces a ‘physiological’ form of cardiac hypertrophy with enhanced coronary angiogenesis and maintained contractility. Here we tested the hypothesis that induction of physiological hypertrophy by short-term Akt activation might improve contractile function in failing hearts. When Akt signaling was transiently activated in murine hearts with impaired contractility induced by pressure overload or adriamycin treatment, contractile dysfunction was attenuated in both cases. Importantly, improvement of contractility was observed before the development of cardiac hypertrophy, indicating that Akt improves contractile dysfunction independently of its growth-promoting effects. To gain mechanistic insights into Akt-mediated positive inotropic effects, transcriptional profiles in the heart were determined in a pressure overload-induced heart failure model. Biological network analysis of differentially expressed transcripts revealed significant alterations in the expression of genes associated with cell death, and these alterations were reversed by short-term Akt activation. Thus, short-term Akt activation improves contractile dysfunction in failing hearts. This beneficial effect of Akt on contractility is hypertrophy-independent and may be mediated in part by inhibition of cell death associated with heart failure. Keywords: transgenic mice, Akt1, cardiac hypertrophy after ascending aortic constriction and contractile dysfunction, DNA microarrays
2019-07-01 | GSE4728 | GEO
Project description:Background ELMSAN1 is a newly identified scaffolding protein of the mitotic deacetylase complex (MiDAC), playing a pivotal role in early embryonic development. Studies on Elmsan1 knockout mice showed that its absence results in embryo lethality and heart malformation. However, the precise function of ELMSAN1 in heart development and formation has remained elusive. To gain insights into its potential role in cardiac lineage, we employed human-induced pluripotent stem cells (hiPSCs) to model early cardiogenesis and investigated the function of ELMSAN1. Methods and Results We generated ELMSAN1-deficient hiPSCs through both knockdown and knockout, revealing that ELMSAN1 appears to be unnecessary for hiPSC maintenance. During the process of cardiac differentiation, ELMSAN1 depletion led to a delay in pluripotency deactivation, decreased expression of cardiac-specific markers, and reduced differentiation efficiency. The impaired expression of genes associated with contractile sarcomere structure, calcium handling, and ion channels were also noted in ELMSAN1-deficient cardiomyocytes derived from hiPSCs (hiPSC-CMs). Additionally, through a series of structural and functional assessments, we found that these cells are immature, exhibiting incomplete sarcomere Z-line structure and length, decreased calcium amplitude, increased time to peak value, faster beat rate with a shorter beat period, decreased field potential duration, and prolonged propagation delay. Of note, we found that the cardiac specific role of ELMSAN1 is likely associated with histone H3K27 acetylation level. The transcriptome analysis provided additional insights, indicating maturation reduction with energy metabolism switch and restored cell proliferation in ELMSAN1 knockout cardiomyocytes. Conclusions In this study, we address the significance of the direct involvement of ELMSAN1 in the differentiation and maturation of hiPSC-CMs. We first report the impact of ELMSAN1 on multiple aspects of hiPSC-CM generation, including cardiac differentiation, sarcomere formation, calcium handling, electrophysiological maturation and proliferation.
2024-07-25 | GSE262838 | GEO
Project description:Cardiomyocyte maturation is the final stage of heart development, and abnormal cardiomyocyte maturation will lead to serious heart diseases. CXXC zinc finger protein 1 (Cfp1) is an important epigenetic factor, which plays an essential role in the development and maturation of multi-lineage cells, while its effect on the maturation of cardiomyocyte remains unclear. This study was performed to explore the potential role of Cfp1 in cardiomyocyte maturation of heart and the underlying mechanisms. Cardiomyocyte-specific Cfp1 knockout (Cfp1-cKO) mice died within 4 weeks of birth. Cardiomyocytes from Cfp1-cKO mice showed an inhibited maturation phenotype in structure, metabolism, contractile function, and cell cycle, accompanied by down-regulation of adult genes and up-regulation of fetal genes. In contrast, cardiomyocyte-specific Cfp1 transgenic (Cfp1-TG) mice and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) overexpressing Cfp1 showed a more mature phenotype. Mechanistically, deficiency of Cfp1 results in reduced trimethylation on lysine 4 of histone H3 (H3K4me3) modification and formation of ectopic H3K4me3. Moreover, Cfp1 deletion decreased the level of H3K4me3 modification in adult genes and increased the level of H3K4me3 modification in fetal genes. Collectively, Cfp1 modulates the expression of cardiomyocyte maturation related genes by modulating histone H3K4me3 modification, which in turn regulates cardiomyocyte maturation. This study implicates Cfp1 as an important molecule regulating cardiomyocyte maturation, and its dysfunction is strongly associated with cardiac disease.
2024-03-27 | GSE240852 | GEO