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PPARdelta signaling induces metabolic maturation in human pluripotent stem cell-derived cardiomyocytes

ABSTRACT: PPARdelta signaling induces metabolic maturation in human pluripotent stem cell-derived cardiomyocytes

PROVIDER: PRJNA675079 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12999500_1.fastq.gz	Fastqsanger.gz
	SRR12999500_2.fastq.gz	Fastqsanger.gz
	SRR12999600_1.fastq.gz	Fastqsanger.gz
	SRR12999600_2.fastq.gz	Fastqsanger.gz
	SRR12999501_1.fastq.gz	Fastqsanger.gz

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PPARdelta signaling induces metabolic maturation in human pluripotent stem cell-derived cardiomyocytes

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

PPARdelta signaling activation improves metabolic and contractile maturation of human pluripotent stem cell-derived cardiomyocytes

Project description:PPARdelta signaling activation improves metabolic and contractile maturation of human pluripotent stem cell-derived cardiomyocytes

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PPARdelta signaling activation improves metabolic and contractile maturation of human pluripotent stem cell-derived cardiomyocytes

2022-04-09 | GSE178984 | GEO

Metabolomics Identifies Metabolic Markers of Maturation in Human Pluripotent Stem Cell-Derived Cardiomyocytes

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.

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Unbiased Proteomics Benchmarking of Maturation of Human Pluripotent Stem Cell-Derived Cardiomyocytes

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.

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Project description:Cardiac tissue constructs from human induced pluripotent stem cells (hiPSCs) have been heralded for their possibilities to serve as disease models, utilized in drug screening and cardiac regeneration. That potential remains to be realized because human iPSC derived cardiomyocytes (hiPSC-CMs) are immature, and do not reflect the characteristics of adult human myocytes. Here, we present a method to accelerate hiPSC-CM maturation by maintaining them on a substrate, Cardiac Mimetic Matrix (CMM), which mimics the adult human heart matrix ligand chemistry and submicron ultrastructure.

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