Prerequisite endocardial-mesenchymal transition for cardiac trabecular angiogenesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA844963 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19542914.fastq.gz | Fastqsanger.gz | |||
| SRR19542915.fastq.gz | Fastqsanger.gz | |||
| SRR19542916.fastq.gz | Fastqsanger.gz | |||
| SRR19542917.fastq.gz | Fastqsanger.gz | |||
| SRR22544061.fastq.gz | Fastqsanger.gz |
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Project description:We used single cell RNA sequencing (scRNAseq) to show that ventricular endocardial cells generate trabecular vessels through an angioEMT mechanism.
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Project description:Coronary heart disease damages the trabecular myocardium, and the regeneration of trabecular vessels may alleviate ischemic injury. However, the origins and developmental mechanisms of trabecular vessels remain unknown. Here, we show that murine ventricular endocardial cells generate trabecular vessels through an "angioEMT" mechanism. Time course fate mapping defined a specific wave of trabecular vascularization by ventricular endocardial cells. Single-cell transcriptomics and immunofluorescence identified a subpopulation of ventricular endocardial cells that underwent endocardial-mesenchymal transition (EMT) before these cells generated trabecular vessels. Ex vivo pharmacological activation and in vivo genetic inactivation experiments identified an EMT signal in ventricular endocardial cells involving SNAI2-TGFB2/TGFBR3, which was a prerequisite for later trabecular-vessel formation. Additional loss- and gain-of-function genetic studies showed that VEGFA-NOTCH1 signaling regulated post-EMT trabecular angiogenesis by ventricular endocardial cells. Our finding that trabecular vessels originate from ventricular endocardial cells through a two-step angioEMT mechanism could inform better regeneration medicine for coronary heart disease.
| S-EPMC10656710 | biostudies-literature
Project description:The ang1-Tie2 pathway is required for normal vascular development, but its molecular effectors are not well-defined during cardiac ontogeny. Here we show that endocardial specific attenuation of Tie2 results in mid-gestation lethality due to heart defects associated with a hyperplastic but simplified trabecular meshwork (fewer but thicker trabeculae). Reduced proliferation and production of endocardial cells (ECs) following endocardial loss of Tie2 results in decreased endocardial sprouting required for trabecular assembly and extension. The hyperplastic trabeculae result from enhanced proliferation of trabecular cardiomyocyte (CMs), which is associated with upregulation of Bmp10, increased retinoic acid (RA) signaling, and Erk1/2 hyperphosphorylation in the myocardium. Intriguingly, myocardial phenotypes in Tie2-cko hearts could be partially rescued by inhibiting in utero RA signaling with pan-retinoic acid receptor antagonist BMS493. These findings reveal two complimentary functions of endocardial Tie2 during ventricular chamber formation: ensuring normal trabeculation by supporting EC proliferation and sprouting, and preventing hypertrabeculation via suppression of RA signaling in trabecular CMs.
2019-05-07 | GSE130741 | GEO
Project description:We established a differentiation strategy to generate endocardial-like cells from hPSCs. Endocardial-like cells generated from our protocol display major functional properties of endocardium in developing embryo: they can induce trabecular markers in early hPSC-derived ventricular cardiomyocytes and they can undergo endothelial-to-mesenchymal-trasition under appropriate conditions. Furthermore, the transcriptome of our in vitro generated endocardial cells showed a very high level of correlation to that of primary fetal endocardial cells. Functional properties and transcriptional profile of hPSC-derived endocardial cells were also compared to those of control (non-endocardial) endothelial cells. For scRNA-seq analysis live cells from bulk endocardial and control endothelial differentiation cultures were labeled with two different sets of anti-human Hashtag antibodies before sequencing. Single cell RNA sequencing was carried out on a sample consisting of 85% bulk endocardial cells (TotalSeq-A0255 anti-human Hashtag 5 antibody, BioLegend) and 15% bulk control endothelial cells (TotalSeq-A0254 anti-human Hashtag 4, Biolegend).
2020-11-02 | GSE151186 | GEO
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Project description:Hypoplastic left heart syndrome (HLHS) is one of the most devastating forms of congenital heart defects. Previous studies have only focused on intrinsic defects in the myocardium. However, this does not sufficiently explain the abnormal development of the cardiac valve, septum, and vasculature, which are known to originate from the endocardium. Here, using single-cell RNA profiling, induced pluripotent stem cells, and fetal heart tissue with an underdeveloped left ventricle, we identified a developmentally impaired endocardial cell population in HLHS. The intrinsic endocardial deficits contributed to abnormal endothelial to mesenchymal transition, NOTCH signaling, and extracellular matrix organization, all of which are key factors in valve formation. Consequentially, endocardial abnormalities conferred reduced proliferation and maturation of cardiomyocytes through a disrupted fibronectin-integrin interaction. Several known HLHS de novo mutations all contributed to the abnormal endocardial gene expression through the alteration of promoter/enhancer activities. These mechanistic discoveries provide an alternative angle for early intervention and heart regeneration in HLHS.
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Project description:Objective: We developed an unbiased strategy to identify genes important in endocardial epithelial-to-mesenchymal transformation (EMT) using a spatial transcriptional profile. Methods and Results: Endocardial cells overlaying the cushions of the atrioventricular canal (AVC) and outflow tract (OFT) undergo an EMT to yield VICs. RNA sequencing (RNA-seq) analysis of gene expression between AVC, OFT, and ventricles (VEN) isolated from chick and mouse embryos at comparable stages of development (chick HH18; mouse E11.0) was performed. EMT occurs in the AVC and OFT cushions, but not VEN at this time. 210 genes in the chick (n=1) and 105 genes in the mouse (n=2) were enriched 2-fold in the cushions. Gene regulatory networks (GRN) generated from cushion-enriched gene lists confirmed TGFβ as a nodal point and identified NF-κB as a potential node. To reveal previously unrecognized regulators of EMT four candidate genes, Hapln1, Id1, Foxp2, and Meis2, and a candidate pathway, NF-κB, were selected. In vivo spatial expression of each gene was confirmed by in situ hybridization and a functional role for each in endocardial EMT was determined by siRNA knockdown in a collagen gel assay. Conclusions: Our spatial-transcriptional profiling strategy yielded gene lists which reflected the known biology of the system. Further analysis accurately identified and validated previously unrecognized novel candidate genes and the NF-κB pathway as regulators of endocardial cell EMT in vitro. 3 separate regions of the developing heart tube were dissected and processed for RNA sequencing analysis in both HH18 chick and E11.0 ICR mouse (done in duplicate)
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Project description:Next-generation sequencing (NGS) has significantly advanced the elucidation of developmental signaling mechanisms that are important for different cell lineage formation from human pluripotent stem cells (hPSCs). We report here the application of RNA-sequencing technology for transcriptome profile of human primary cardiac microvascular endothelial cells and hPSC-derived endocardial endothelial cells, and compare to those of other cell lineages including hPSCs, mesoderm, cardiomcyotyes as well as mouse cardiac microvascular and endocardial endothelial cells. Six cardiac endothelial cell samples from two different hPSC lines and one donor were performed in IIIumina HiSeq2500. The resulting sequence reads (about 20 million reads per sample) were mapped to human genome (hg19) using HISAT, and the RefSeq transcript levels (RPKMs) were quantified using the python script rpkmforgenes.py. Our RNA-seq data confirmed the stable expression of key endocardial endothelial cell markers including CDH5, vWF, PECAM1, NFATC1 and NPR3, and the gene set enrichment analysis (GSEA) showed enrichment in angiogenesis and vasculature development. Hierarchical clustering of differentially expressed genes uncovered several as yet uncharacterized genes that may contribute to endocardial function. This study represents the first detailed analysis of endocardial-like endothelial cell transcriptomes generated by RNA-seq technology, providing insight into the mechanisms underlying the differentiation of hPSCs into endocardium.
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Project description:The endocardium interacts with the myocardium to promote proliferation and morphogenesis during the later stages of heart development. However, the role of the endocardium in early cardiac ontogeny remains under-explored. Given the shared origin, subsequent juxtaposition, and essential cell-cell interactions of endocardial and myocardial cells throughout heart development, we hypothesized that paracrine signaling from the endocardium to the myocardium is critical for initiating early differentiation of myocardial cells. To test this, we generated an in vitro, endocardial-specific ablation model using the diphtheria toxin receptor under the regulatory elements of the NFATc1 genomic locus (NFATc1-DTR) Early treatment of NFATc1-DTR embryoid bodies with diphtheria toxin efficiently ablated endocardial cells, which significantly attenuated the percent of beating EBs in culture and expression of early and late myocardial differentiation markers. The addition of Bmp2 during endocardial ablation partially rescued myocyte differentiation, maturation and function. Therefore, we conclude that early stages of myocardial differentiation rely on endocardial paracrine signaling mediated in part by Bmp2. Our findings provide novel insight into early endocardial-myocardial interactions that can be explored to promote early myocardial development and growth.
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