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EPICARDIOID SINGLE-CELL GENOMICS UNCOVER PRINCIPLES OF HUMAN EPICARDIUM BIOLOGY IN HEART DEVELOPMENT AND DISEASE [scRNA-Seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE196513 | GEO | 2023/02/05

REPOSITORIES: GEO

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EPICARDIOID SINGLE-CELL GENOMICS UNCOVER PRINCIPLES OF HUMAN EPICARDIUM BIOLOGY IN HEART DEVELOPMENT AND DISEASE [scATAC-Seq]

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

Genome-wide analysis of epicardial gene expression in E11.5 mouse hearts

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

Comparative transcriptomic analysis of human epicardial progenitor cells and hiPSC-derived cardiac progenitor cells under hypoxic and normoxic culture conditions

Project description:The adult mammalian heart has been traditionally regarded as a post-mitotic organ with no regenerative capacity. However, this dogma has been refuted by some recent landmark studies. Both cardiac progenitor cells (CPCs) and epicardial progenitor cells (EPDCs) are activated after myocardium infarction and they may influence each other through paracrine mechanisms or direct interactions. Currently, efforts are being made to discover and develop therapeutic molecules to increase the number of CPCs and EPDCs in an infarcted heart. To better understand the characteristics and therapeutic potential of CPCs and EPDCs, as well as the regulatory mechanisms, we performed transcriptomic analysis of human iPSC-derived CPCs and human primary EPDCs and discovered unique gene expression profiles for each cell type. To make sure that the biological and pharmacological findings in cell assays under ambient oxygen conditions are relevant to the in vivo situation, it is important to understand the effect of hypoxia on the behavior, gene expression, and paracrine profiles of the cells. <br>Comparative transcriptomic analysis of human epicardial progenitor cells and hiPSC-derived cardiac progenitor cells was conducted. We performed global transcriptional analysis of two sources of cardiac progenitors, i.e., patient epicardium-derived cells (EPDCs) and cardiac progenitor cells (CPCs) derived from human induced pluripotent stem cells. In addition, we also compared the gene expression profiles of these cells when they were cultured under normoxic- and hypoxic conditions.

2016-06-27 | E-MTAB-4609 | biostudies-arrayexpress

Functional heterogeneity within the developing zebrafish epicardium

Project description:The epicardium is essential during cardiac development, homeostasis and repair and yet fundamental insights into its underlying cell biology, notably epicardium formation, lineage heterogeneity and functional cross-talk with other cell types in the heart, is currently lacking. In this study, we investigated epicardial heterogeneity and the functional diversity of discrete epicardial subpopulations in the developing zebrafish heart. Single-cell RNA-sequencing uncovered three epicardial subpopulations with specific genetic programmes and distinctive spatial distribution within the developing heart. Perturbation of unique gene signatures uncovered distinct functions associated with each subpopulation and established novel epicardial roles in cell adhesion, migration, and chemotaxis as a mechanism for recruitment of leukocytes into the heart. This work elucidates the mutual spatiotemporal relationships between different epicardial subpopulations and assigns unique function to each during cardiac development. Understanding which mechanisms cells employ to establish a functional epicardium and to communicate with other cardiovascular cell types during development will bring us closer to repairing cellular relationships that are disrupted during cardiovascular disease.

2020-01-20 | GSE121750 | GEO

Single epicardial cell transcriptome sequencing identifies Caveolin-1 as an essential factor in zebrafish heart regeneration

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

A single-cell comparison of adult and foetal human epicardium defines the age-associated changes in epicardial activity

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

Identification of Tcf21 downstream genes in the epicardial cells and cardiomyocytes by transcriptomic analysis

Project description:Purpose: Studying the epicardium-myocardium crosstalk in the zebrafish larval heart. To do so, we aimed to identify, with RNA-seq, the genes dysregulated following the loss of the epicardial marker gene tcf21 in sorted epicardial cells and cardiomyocytes. Results: We first analyzed the transcriptome of epicardial and myocardial WT cells and identified cell-type specific/enriched genes. Then, we identified several differential expressed genes in tcf21 mutants, including several ligand-receptor couples known to mediate the epicardium-myocardium crosstalk.

2022-10-12 | GSE174505 | GEO

Genome-wide analysis of epicardial gene expression in E11.5 mouse hearts

2012-11-01 | GSE41959 | GEO

Comparing a timecourse of hESC-epicardium differentiation with single-cell adult and foetal human epicardium as part of the study: A single-cell comparison of adult and foetal human epicardium defines the age-associated changes in epicardial activity

Project description:This study is associated with the GEO accession GSE216019. Abstract from article: 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 endpoints required for effective human heart regeneration.

2022-10-31 | GSE216177 | GEO

Nonmuscle myosin IIB regulates epicardial integrity and epicardium-derived mesenchymal cell maturation

Project description:Nonmuscle myosin IIB (NMIIB; heavy chain encoded by MYH10) is essential for cardiac myocyte cytokinesis. The role of NMIIB in other cardiac cells is not known. Here, we show that NMIIB is required in epicardial formation and functions to support myocardial proliferation and coronary vessel development. Ablation of NMIIB in epicardial cells results in disruption of epicardial integrity with a loss of E-cadherin at cell-cell junctions and a focal detachment of epicardial cells from the myocardium. NMIIB-knockout and blebbistatin-treated epicardial explants demonstrate impaired mesenchymal cell maturation during epicardial epithelial-mesenchymal transition. This is manifested by an impaired invasion of collagen gels by the epicardium-derived mesenchymal cells and the reorganization of the cytoskeletal structure. Although there is a marked decrease in the expression of mesenchymal genes, there is no change in Snail (also known as Snai1) or E-cadherin expression. Studies from epicardium-specific NMIIB-knockout mice confirm the importance of NMIIB for epicardial integrity and epicardial functions in promoting cardiac myocyte proliferation and coronary vessel formation during heart development. Our findings provide a novel mechanism linking epicardial formation and epicardial function to the activity of the cytoplasmic motor protein NMIIB.

2017-07-21 | GSE101701 | GEO

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