Single-cell transcriptional analysis of developmental maturation strategies for human pluripotent stem cell-derived heart organoids
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE218582 | GEO | 2023/11/21
REPOSITORIES: GEO
Similar Datasets
Project description:During cardiac development, cells from the precardiac mesoderm fuse to form the primordial heart tube, which then grows by addition of further progenitors to the venous and arterial poles. In the zebrafish, wilms tumor 1 transcription factor a (wt1a) and b (wt1b) are expressed in the pericardial mesoderm at the venous pole of the forming heart tube. The pericardial mesoderm forms a single layered mesothelial sheet that contributes to further the growth of the myocardium, and forms the proepicardium. Proepicardial cells are subsequently transferred to the myocardial surface and give rise to the epicardium, the outer layer covering the myocardium in the adult heart. wt1a/b expression is downregulated during the transition from pericardium to myocardium, but remains high in proepicardial cells. Here we show that sustained wt1 expression impaired cardiomyocyte maturation including sarcomere assembly, ultimately affecting heart morphology and cardiac function. ATAC-seq data analysis of cardiomyocytes overexpressing wt1 revealed that chromatin regions associated with myocardial differentiation genes remain closed upon wt1b overexpression in cardiomyocytes, suggesting that wt1 represses a myocardial differentiation program. Indeed, a subset of wt1a/b-expressing cardiomyocytes changed their cell adhesion properties, delaminated from the myocardial epithelium, and upregulated the expression of epicardial genes, as confirmed by in vivo imaging. Thus, we conclude that wt1 acts as a break for cardiomyocyte differentiation by repressing chromatin opening at specific genomic loci and that sustained ectopic expression of wt1 in cardiomyocytes can lead to their transformation into epicardial cells.
2022-03-08 | GSE179521 | GEO
Project description:During cardiac development, cells from the precardiac mesoderm fuse to form the primordial heart tube, which then grows by addition of further progenitors to the venous and arterial poles. In the zebrafish, wilms tumor 1 transcription factor a (wt1a) and b (wt1b) are expressed in the pericardial mesoderm at the venous pole of the forming heart tube. The pericardial mesoderm forms a single layered mesothelial sheet that contributes to further the growth of the myocardium, and forms the proepicardium. Proepicardial cells are subsequently transferred to the myocardial surface and give rise to the epicardium, the outer layer covering the myocardium in the adult heart. wt1a/b expression is downregulated during the transition from pericardium to myocardium, but remains high in proepicardial cells. Here we show that sustained wt1 expression impaired cardiomyocyte maturation including sarcomere assembly, ultimately affecting heart morphology and cardiac function. ATAC-seq data analysis of cardiomyocytes overexpressing wt1 revealed that chromatin regions associated with myocardial differentiation genes remain closed upon wt1b overexpression in cardiomyocytes, suggesting that wt1 represses a myocardial differentiation program. Indeed, a subset of wt1a/b-expressing cardiomyocytes changed their cell adhesion properties, delaminated from the myocardial epithelium, and upregulated the expression of epicardial genes, as confirmed by in vivo imaging. Thus, we conclude that wt1 acts as a break for cardiomyocyte differentiation by repressing chromatin opening at specific genomic loci and that sustained ectopic expression of wt1 in cardiomyocytes can lead to their transformation into epicardial cells.
2022-03-08 | GSE179520 | GEO
Project description:Identification of epicardium-enriched genes in the embryonic heart. The epicardium encapsulates the heart and functions as a source of multipotent progenitor cells and paracrine factors essential for cardiac development and repair. Injury of the adult heart results in re-activation of a developmental gene program in the epicardium, but the transcriptional basis of epicardial gene expression has not been delineated. We established a mouse embryonic heart organ culture and gene expression system that facilitated the identification of epicardial enhancers activated during heart development and injury. Epicardial activation of these enhancers depends on a combinatorial transcriptional code centered on CCAAT/enhancer binding protein (C/EBP) transcription factors. Disruption of C/EBP signaling in the adult epicardium reduced injury-induced neutrophil infiltration and improved cardiac function. These findings reveal a transcriptional basis for epicardial activation and heart injury, providing a platform for enhancing cardiac regeneration. Total RNA obtained from lacZ-positive epicardial cells isolated from the E11.5 Tcf21lacZ hearts compared to total dissociated heart cells
2012-11-01 | E-GEOD-41959 | biostudies-arrayexpress
Project description:Epicardial cells can undergo epithelium-to-mesenchymal transition (EMT) upon which the epicardium-derived cells (EPDCs) migrate into the myocardium and deliver growth factors or differentiate into smooth muscle cells or fibroblasts. The cell fate of EPDCs has been proposed to be determined by the persistence of subpopulations found in the proepicardial organ, but findings regarding this epicardial heterogeneity have been inconsistent. In the human heart, the composition of the developing epicardium is largely unknown. Here we performed a direct analysis of the human fetal epicardium through single cell RNA sequencing to investigate its composition and to search for regulators of developmental processes
2023-06-29 | GSE213669 | GEO
Project description:Native human epicardial precursors are virtually inaccessible, as they appear in the embryo less than four weeks post-conception, at which point pregnancy may not yet be detected. Protocols have been established to generate epicardial cells and their progeny from human pluripotent stem cells in vitro. However, no current model is amenable to studying the many facets of human epicardial biology, notably epicardium formation, lineage heterogeneity, and functional crosstalk with other cardiac cell types during organ development and disease. Here, we generated human pluripotent stem cell-derived 3D heart organoids showing retinoic acid-dependent self-organization of the epicardium and myocardium, which we called epicardioids. Time course single-cell RNA sequencing revealed that epicardioids are formed through the specification of first heart field progenitors, a subset of which closely correspond to juxta-cardiac field (JCF) cells that have recently been identified in the embryonic mouse heart as novel common progenitors of myocardium and epicardium and have not yet been described and studied in humans. Analysis of chromatin accessibility by single-cell ATAC-seq additionally revealed key transcriptional programs guiding fate decisions along the epicardial lineage tree. Human epicardioids provide a unique model to gain fundamental insights into human epicardium biology and function during heart development, homeostasis, and disease.
2023-02-05 | GSE196513 | GEO
Project description:Native human epicardial precursors are virtually inaccessible, as they appear in the embryo less than four weeks post-conception, at which point pregnancy may not yet be detected. Protocols have been established to generate epicardial cells and their progeny from human pluripotent stem cells in vitro. However, no current model is amenable to studying the many facets of human epicardial biology, notably epicardium formation, lineage heterogeneity, and functional crosstalk with other cardiac cell types during organ development and disease. Here, we generated human pluripotent stem cell-derived 3D heart organoids showing retinoic acid-dependent self-organization of the epicardium and myocardium, which we called epicardioids. Time course single-cell RNA sequencing revealed that epicardioids are formed through the specification of first heart field progenitors, a subset of which closely correspond to juxta-cardiac field (JCF) cells that have recently been identified in the embryonic mouse heart as novel common progenitors of myocardium and epicardium and have not yet been described and studied in humans. Analysis of chromatin accessibility by single-cell ATAC-seq additionally revealed key transcriptional programs guiding fate decisions along the epicardial lineage tree. Human epicardioids provide a unique model to gain fundamental insights into human epicardium biology and function during heart development, homeostasis, and disease.
2023-02-05 | GSE196512 | GEO
Project description:By contrast with mammals, adult zebrafish have a high capacity to regenerate damaged or lost myocardium through proliferation of spared cardiomyocytes. The epicardial sheet covering the heart is activated by injury and aids muscle regeneration through paracrine effects and as a multipotent cell source, and has received recent attention as a target in cardiac repair strategies. While it is recognized that epicardium is required for muscle regeneration and itself has high regenerative potential, the extent of cellular heterogeneity within epicardial tissue is largely unexplored. In this study, we performed transcriptome analysis on dozens of epicardial lineage cells purified from zebrafish harboring a transgenic reporter for the pan-epicardial gene tcf21. Hierarchical clustering analysis suggested the presence of at least three epicardial cell subsets defined by expression signatures. We validated many new pan-epicardial and epicardial markers by alternative expression assays. Additionally, we explored the function of the scaffolding protein and main component of caveolae, caveolin-1 (cav1), which was present in each epicardial subset. In BAC transgenic zebrafish, cav1 regulatory sequences drove strong expression in ostensibly all epicardial cells and in coronary vascular endothelial cells. Moreover, cav1 mutant zebrafish generated by genome editing showed grossly normal heart development and adult cardiac anatomy, but displayed profound defects in injury-induced cardiomyocyte proliferation and heart regeneration. Our study defines a new platform for the discovery of epicardial lineage markers, genetic tools, and mechanisms of heart regeneration. Deep sequencing of isolated single epicardial cells
2015-12-15 | E-GEOD-75583 | biostudies-arrayexpress
Project description:Identification of epicardium-enriched genes in the embryonic heart. The epicardium encapsulates the heart and functions as a source of multipotent progenitor cells and paracrine factors essential for cardiac development and repair. Injury of the adult heart results in re-activation of a developmental gene program in the epicardium, but the transcriptional basis of epicardial gene expression has not been delineated. We established a mouse embryonic heart organ culture and gene expression system that facilitated the identification of epicardial enhancers activated during heart development and injury. Epicardial activation of these enhancers depends on a combinatorial transcriptional code centered on CCAAT/enhancer binding protein (C/EBP) transcription factors. Disruption of C/EBP signaling in the adult epicardium reduced injury-induced neutrophil infiltration and improved cardiac function. These findings reveal a transcriptional basis for epicardial activation and heart injury, providing a platform for enhancing cardiac regeneration.
2012-11-01 | GSE41959 | GEO
Project description:Re-activating quiescent adult epicardium represents a potential therapeutic approach for human cardiac regeneration. However, the exact molecular differences between inactive adult and active foetal epicardium are not known. Here, we combined foetal and adult human hearts for the first time using single-cell and single-nuclei RNA sequencing, and compared epicardial cells from both stages. We found a migratory fibroblast-like epicardial population only in the foetal heart and foetal epicardium expressed angiogenic gene programs, while the adult epicardium was solely mesothelial and immune-responsive. Furthermore, we predicted that adult hearts may still receive foetal epicardial paracrine communication, including WNT-signalling with endocardium, reinforcing the validity of regenerative strategies that administer or reactivate epicardial cells in situ. Finally, we explained graft efficacy of our human embryonic stem-cell derived epicardium model, by noting its similarity to human foetal epicardium. Overall, our study defines epicardial programs of regenerative angiogenesis absent in adult hearts, contextualises animal studies, and defines epicardial states required for effective human heart regeneration.
2022-10-31 | GSE216019 | GEO
Project description:Exploring the mechanisms of valvular heart disease (VHD) at the cellular level may be useful to identify new therapeutic targets; however, the comprehensive cellular landscape of non-diseased human cardiac valve leaflets remains unclear. The cellular landscapes of non-diseased human cardiac valve leaflets (five aortic valves, five pulmonary valves, five tricuspid valves, and three mitral valves) from end-stage heart failure patients undergoing heart transplantation were explored using single-cell RNA sequencing (scRNA-seq)
2022-09-13 | GSE213128 | GEO