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Maturation of human cardiac organoids enables complex disease modelling and drug discovery

ABSTRACT: Maturation of human cardiac organoids enables complex disease modelling and drug discovery

PROVIDER: PRJNA1211166 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32015257.fastq.gz	Fastqsanger.gz
	SRR32015258.fastq.gz	Fastqsanger.gz
	SRR32015259.fastq.gz	Fastqsanger.gz
	SRR32015260.fastq.gz	Fastqsanger.gz
	SRR32015261.fastq.gz	Fastqsanger.gz

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Maturation of human cardiac organoids enables complex disease modelling and drug discovery

Project description:Cardiac maturation is an important developmental phase culminating in profound biological and functional changes to adapt to the high demand environment after birth. Maturation of human pluripotent stem cell-derived human cardiac organoids (hCO) to more closely resemble human heart tissue is critical for understanding disease pathology. Herein, we profile human heart maturation in vivo to identify key signalling pathways that drive maturation in hCOs. Transient activation of both the 5’ AMP-activated kinase (AMPK) and estrogen-related receptor (ERR) promoted hCO maturation by mimicking the increased functional demands of post-natal development. hCOs cultured under these directed maturation (DM) conditions (DM-hCOs) display robust transcriptional maturation including increased expression of mature sarcomeric and oxidative phosphorylation genes resulting in enhanced metabolic capacity. DM-hCOs have functionally mature properties such as sarcoplasmic reticulum-dependent calcium handling, accurate responses to drug treatments perturbing the excitation-coupling process and ability to detect ectopy CASQ2 and RYR2 mutants. Importantly, DM-hCOs permit modelling of complex human disease processes such as desmoplakin (DSP) cardiomyopathy, which is driven by multiple cell types. Subsequently, we deploy DM-hCOs to demonstrate that bromodomain extra-terminal inhibitor INCB054329 rescues the DSP phenotype. Together, this study demonstrates that recapitulating in vivo development promotes advanced maturation enabling disease modelling and the identification of a therapeutic strategy for DSP-cardiomyopathy.

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A novel CRISPR activation mouse enables modelling of aggressive lymphoma and interrogation of venetoclax resistance

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Decoding the Long Noncoding RNA during Cardiac Maturation: a Roadmap for Functional Discovery [lncRNA]

Project description:Cardiac maturation during perinatal transition of heart is critical for functional adaptation to hemodynamic load and nutrient environment. Perturbation in this process has major implications in congenital heart defects (CHDs). Transcriptome programming during perinatal stages is important information but incomplete in current literature, particularly, the expression profiles of the long noncoding RNAs (lncRNAs) are not fully elucidated From comprehensive analysis of transcriptomes derived from neonatal mouse heart left and right ventricles, a total of 45,167 unique transcripts were identified, including 21,916 known and 2,033 novel lncRNAs. Among these lncRNAs, 196 exhibited significant dynamic regulation along maturation process. By implementing parallel weighted gene co-expression network analysis (WGCNA) of mRNA and lncRNA datasets, several lncRNA modules coordinately expressed in a developmental manner similar to protein coding genes, while a few of them revealed chamber specific patterns. Out of 2,442 lncRNAs located within 50 KBs of protein coding genes, 11% significantly correlates with the expression of their neighboring genes. The impact of Ppp1r1b-lncRNA on the corresponding partner gene Tcap was validated in cultured myoblasts. While this concordant regulation was also conserved in human infantile hearts. Furthermore, the Ppp1r1b-lncRNA/Tcap expression ratio was identified as a molecular signature that differentiated CHD phenotypes lncRNA dataset: neonatal mouse heart left and right ventricles

2016-08-20 | E-GEOD-85726 | biostudies-arrayexpress

Decoding the Long Noncoding RNA during Cardiac Maturation: a Roadmap for Functional Discovery [RNA]

Project description:Cardiac maturation during perinatal transition of heart is critical for functional adaptation to hemodynamic load and nutrient environment. Perturbation in this process has major implications in congenital heart defects (CHDs). Transcriptome programming during perinatal stages is important information but incomplete in current literature, particularly, the expression profiles of the long noncoding RNAs (lncRNAs) are not fully elucidated From comprehensive analysis of transcriptomes derived from neonatal mouse heart left and right ventricles, a total of 45,167 unique transcripts were identified, including 21,916 known and 2,033 novel lncRNAs. Among these lncRNAs, 196 exhibited significant dynamic regulation along maturation process. By implementing parallel weighted gene co-expression network analysis (WGCNA) of mRNA and lncRNA datasets, several lncRNA modules coordinately expressed in a developmental manner similar to protein coding genes, while a few of them revealed chamber specific patterns. Out of 2,442 lncRNAs located within 50 KBs of protein coding genes, 11% significantly correlates with the expression of their neighboring genes. The impact of Ppp1r1b-lncRNA on the corresponding partner gene Tcap was validated in cultured myoblasts. While this concordant regulation was also conserved in human infantile hearts. Furthermore, the Ppp1r1b-lncRNA/Tcap expression ratio was identified as a molecular signature that differentiated CHD phenotypes RNA dataset: neonatal mouse heart left and right ventricles

2016-08-20 | E-GEOD-85727 | biostudies-arrayexpress

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Project description:Cardiac maturation is an important developmental phase where there are profound biological and functional changes after birth in mammals. Herein, we use our profiling of human heart maturation in vivo to identify key drivers of maturation in our human cardiac organoid (hCO) model. After screening of various metabolism modulating factors, we established a directed maturation protocol to induce mature cardiac expression. We next compared directed maturation treatment to electrical pacing using phosphoproteomics in order to assess the similarities in the induction of maturation. The electrical pacing protocol utilized a custom platform, where we added Heart-Dyno inserts into C-pace system in 24-well plates enabling 120 bpm pacing for 5 minutes without causing toxicity. In this dataset, we compared 3 replicates of CTRL (our original serum free organoid protocol), electrical pacing (the standard protocol for maturation of cardiac stem cells), and directed maturation protocol (DM, new protocol) through phosphoproteomics.

2025-04-17 | PXD054810 | Pride

Cardiac maturation process from human iPSCs

Project description:To improve the maturity of iPSC-cardiomyocytes, we addressed the cell type specification of iPSC-cardiomyocytes by microarray and analyzed in detail about cardiac maturation process. We compared gene expression between samples, and extracted several key genes for cardac maturation and check the function of these genes. We show that a number of genes expression correlate with cardiac maturation process, and found surface markers to discriminate differentiated cardiomyocytes from other immature cells.

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