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Hapln1a+ cells guide coronary growth during heart morphogenesis and regeneration [Reg, hapln1a+ cell]

ABSTRACT: As cardiac regeneration requires new coronary vessels, exploring the underlying mechanisms behind revascularization will facilitate the development of regenerative therapies for heart failure. Although multiple tissues and chemokines likely orchestrate coronary formation, the interaction between coronary growth and guidance cues remains unclear. Here, by applying single-cell RNA-sequencing (scRNA-seq) analysis, we examined gene expression in zebrafish epicardial cells during coronary vascularization and identified hapln1a-expressing epicardial cells enriched with vascular-regulating genes. Fluorescence reporter assays indicated hapln1a+ cells not only envelop coronary vessels, but also form cellular shear structures in ahead of coronary tips. Live imaging analyses demonstrated coronary growth along the pre-formed shears, with depletion of hapln1a+ cells blocking this growth. Further, we found hapln1a+ cells also pre-lead coronary tips in the regenerating area and hapln1a+ cell loss inhibits coronary revascularization. To characterize the molecular nature of hapln1a+ cells during coronary growth, we profiled hapln1a+ cells in juvenile and regenerating hearts and detected expression of the cell adhesion and migration regulator serpine1 in hapln1a+ cells adjacent to coronary tips. Pharmacological inhibition of serpine1 function blocked coronary vascularization and revascularization. Altogether, our studies reveal that hapln1a+ cells are required for coronary production during heart morphogenesis and regeneration, by establishing a microenvironment to facilitate guided coronary growth.

ORGANISM(S): Danio rerio

PROVIDER: GSE216647 | GEO | 2023/05/26

REPOSITORIES: GEO

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hapln1a+ cells guide coronary growth during heart morphogenesis and regeneration [Dev, hapln1a+ cells]

Project description:As cardiac regeneration requires new coronary vessels, exploring the underlying mechanisms behind revascularization will facilitate the development of regenerative therapies for heart failure. Although multiple tissues and chemokines likely orchestrate coronary formation, the interaction between coronary growth and guidance cues remains unclear. Here, by applying single-cell RNA-sequencing (scRNA-seq) analysis, we examined gene expression in zebrafish epicardial cells during coronary vascularization and identified hapln1a-expressing epicardial cells enriched with vascular-regulating genes. Fluorescence reporter assays indicated hapln1a+ cells not only envelop coronary vessels, but also form cellular shear structures in ahead of coronary tips. Live imaging analyses demonstrated coronary growth along the pre-formed shears, with depletion of hapln1a+ cells blocking this growth. Further, we found hapln1a+ cells also pre-lead coronary tips in the regenerating area and hapln1a+ cell loss inhibits coronary revascularization. To characterize the molecular nature of hapln1a+ cells during coronary growth, we profiled hapln1a+ cells in juvenile and regenerating hearts and detected expression of the cell adhesion and migration regulator serpine1 in hapln1a+ cells adjacent to coronary tips. Pharmacological inhibition of serpine1 function blocked coronary vascularization and revascularization. Altogether, our studies reveal that hapln1a+ cells are required for coronary production during heart morphogenesis and regeneration, by establishing a microenvironment to facilitate guided coronary growth.

2023-05-26 | GSE216646 | GEO

hapln1a+ cells guide coronary growth during heart morphogenesis and regeneration [Dev, tcf21+ cells]

2023-05-26 | GSE216648 | GEO

hapln1 defines an epicardial cell subpopulation that establishes cardiogenic hotspots during heart morphogenesis and regeneration

Project description:The epicardium, a thin mesothelial tissue layer that encompasses the heart, is a dynamic structure that is essential for cardiac regeneration in species with elevated regenerative capacity like zebrafish. To dissect epicardial cell states and associated pro-regenerative functions, we performed single-cell RNA-sequencing and identified 7 epicardial cell clusters in adult zebrafish, with 3 of these clusters enhanced during regeneration. ECM components encoded by hapln1 paralogs label an enriched epicardial cell type that accumulates and encloses dedifferentiated and proliferating cardiomyocytes during regeneration. Genetic inactivation of hapln1b, or induced genetic depletion of hapln1a-expressing cells, disrupted cardiomyocyte proliferation and heart regeneration. hapln1a+ cells first emerge at the juvenile stage, when they associate with and are required for cardiogenic foci that direct growth of the juvenile heart. Our findings identify a subset of epicardial cells that emerges in post-embryonic animals and sponsors regions of active cardiomyogenesis during heart growth and regeneration

2022-06-17 | GSE172511 | GEO

PRMT1-Mdm4-p53 pathway controls epicardial invasion and cell fate transition

Project description:Epicardial cells are progenitors giving rise to the majority of cardiac fibroblasts, coronary smooth muscle cells, and pericytes during cardiac development, and critically modulating heart morphogenesis and coronary development. An integral phase of epicardial cell fate transition is epithelial-to-mesenchymal transition (EMT), which confers motility and facilitates cell fate transition. We identify a pathway involving protein arginine methyltransferase 1 (PRMT1) and its downstream p53 signaling that drives epicardial EMT and invasion. We show that PRMT1 determines the half-life of p53 through regulating alternative splicing of Mdm4, which is a key controller of p53 degradation. Loss of PRMT1 promotes the expression of Mdm4 short form, which inhibits p53 degradation. Accumulation of p53 subsequently enhances Slug degradation and blocks epicardial EMT. We further demonstrated that the PRMT1-Mdm4-p53 pathway drives epicardial cell fate transition into cardiac fibroblasts, coronary smooth muscle cells and pericytes in vivo, and modulates ventricular morphogenesis and coronary vessel formation. Together, our results establish critical functions of the PRMT1-Mdm4-p53 pathway in epicardial EMT, invasion and cell fate transition.

2020-08-18 | GSE122200 | GEO

An injury-associated transient progenitor state in the epicardium mediates heart regeneration

Project description:Adult zebrafish regenerate heart muscle after severe cardiac damage without significant scarring. The epicardium, a mesothelial cell sheet covering the vetebrate heart, is activated by injury and supports muscle regeneration through paracrine effects and as a source of multipotent cells. The understudied cellular heterogeneity of the adult epicardium during heart regeneration has constrained the effort in mobilizing the epicardium for heart repair. To dissect epicardial cell states and the underlying mechanisms that lead to successful heart regeneration in zebrafish, we performed single-cell RNA-sequencing of isolated epicardial cells from the regenerating adult heart and revealed their dynamic cellular heterogeneity. We defined the epithelial and mesenchymal layers of the epicardium and identified a transiently activated epicardial progenitor cell (aEPC) subpopulation that expresses aldh1a2, ptx3a, col12a1b and marcksb. Upon heart amputation injury, aEPCs emerge from the existing epicardial cells, migrate to enclose the wound, and disappear as regeneration progresses. Genetic lineage tracing combined with modified RNA labelling confirmed an epithelial-mesenchymal transition (EMT) process of aEPCs and their differentiations to pdgfrb+ mural cells and pdgfra+hapln1a+ mesenchymal fibroblast-like cells that support heart regeneration. Genetic ablation of aEPCs blocked wound closure of the injured ventricle, suppressed cardiomyocyte proliferation, and disrupted heart regeneration. Our findings define a transient progenitor state of the adult epicardium that is an indispensable driver of zebrafish heart regeneration and identified ptx3a as a regeneration-specific non-ontogenetic regulator of the epicardium.

2022-11-22 | GSE202836 | GEO

Hearts after off-pump coronary revascularization surgery and on-pump coronary artery bypass grafting

Project description:This SuperSeries is composed of the following subset Series: GSE12485: Changes in cardiac transcription profiles following off-pump coronary revascularization surgery GSE12486: Changes in cardiac transcription profiles following on-pump coronary artery bypass grafting Refer to individual Series

2010-07-07 | E-GEOD-12504 | biostudies-arrayexpress

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

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

Expression Data from epicardial (EAT) and subcutaneous adipose tissue (SAT) in patients with coronary artery disease

Project description:We took samples of subcutaneous adipose tissue from the sternum (SAT) and epicardial adipose tissue (EAT) from a site adjacent to the right coronary artery in cases with coronary disease and controls without coronary disease. Cases had significant coronary disease and were undergoing coronary artery bypass surgery. Controls all had coronary angiograms and did not have significant coronary disease.

2018-10-04 | GSE120774 | GEO

Changes in cardiac transcription profiles following off-pump coronary revascularization surgery

Project description:To investigate changes in cardiac transcription profiles caused by off-pump cardiac surgery, we collected myocardial samples, prior and after grafting, from patients undergoing off-pump coronary revascularization surgery. The transcriptional profile of the mRNA in these samples was measured with gene array technology. Changes in transcriptional profiles can be correlated with the stress response of heart to off-pump surgery. Keywords: human, cardiac, OPCAB coronary surgery, gene expression. Myocardial samples were collected, prior and after grafting, from patients undergoing off-pump coronary artery bypass grafting.

2010-07-07 | E-GEOD-12485 | biostudies-arrayexpress

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