Gene expression profile of single endocardial cells in 48 and 72 hpf zebrafish embryos/larvae. In the study "The heart is a niche for hematopoietic stem and progenitor cells in zebrafish."
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ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE269378 | GEO | 2024/07/31
REPOSITORIES: GEO
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Project description:Seeking to identify additional transcription factors required for cardiac valve formation, we determined and explored the transcriptional landscape of endocardial cells at the time when key morphogenetic events underlying valve development take place.
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Project description:Valvular heart disease presents a significant health burden, yet advancements in valve biology and novel therapeutics have been hindered by the lack of accessibility to human valve cells. In this study, we have developed a scalable and feeder-free method to differentiate human induced pluripotent stem cells (iPSCs) into endocardial cells. Importantly, we show that these endocardial cells are transcriptionally and phenotypically distinct from vascular endothelial cells and can be directed to undergo endothelial-to-mesenchymal transition (EndMT) to generate cardiac valve cell populations. Following this, we identified two distinct populations—one population undergoes EndMT to become valvular interstitial cells (VICs), while the other population reinforces their endothelial identity to become valvular endothelial cells (VECs). We then characterized our iPSC-derived cell populations and identified putative markers for these populations through bulk RNAseq transcriptome analyses. Lastly, we validated our VIC and VEC populations by comparing our transcriptomic data to pseudobulk data generated from single-cell RNAseq of normal valve tissue from a 15-week-old human fetus. By increasing the accessibility to these cell populations, we aim to accelerate discoveries for cardiac valve biology and disease.
2023-03-03 | GSE226476 | GEO
Project description:Discreet defects during prenatal semilunar valve (SLV) development frequently progress to pathological states later in life and often require valve replacement surgery. As such, it is challenging to distinguish between the disrupted developmental processes, and their genetic and environmental influences, that trigger valve defects from mechanisms that drive the progression of an anatomically abnormal valve into a disease state. This distinction, which is essential to inform the rationale design of diagnostics and therapeutics, requires carefully characterizing when and where an implicated gene or pathway functions during valve development and/or homeostasis. Disrupted growth, differentiation, and patterning events that trigger SLV disease are coordinated by gene expression changes in endocardial, myocardial, and cushion mesenchymal cells. We explored the roles of chromatin regulation in valve gene regulatory networks via conditional inactivation of the mouse Brg1 associated factor (BAF) chromatin-remodeling complex in the endocardial lineage. Endocardial Brg1-deficient embryos develop thickened and mal-patterned SLV cusps that frequently become bicuspid and myxomatous, including in surviving adults. These SLV disease-like phenotypes originate from deficient endocardial-mesenchymal transformation (EMT) in the proximal outflow tract (pOFT) cushions. Mesenchymal cells of neural crest or other cardiac origins subsequently replace the missing EMT-derived cells but are incompetent to pattern the valve interstitium into regions with distinct extracellular matrix composition. Transcriptomics reveal genes that may promote growth and patterning of SLVs and/or serve as biomarkers of their diseased state. Mechanistic studies of SLV disease genes will distinguish between disease origins and progression; the latter may largely reflect secondary responses to a disrupted developmental system.
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Project description:The variations in the protein profile of aortic-valvular (AVE) and endocardial endothelial (EE) cells are currently unknown. The current study's objective is to identify differentially expressed proteins and associated pathways in both endothelial cells. We used endothelial cells isolated from the porcine aortic valve and endocardium for the profiling of proteins. Label-free proteomics was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Our proteomics analysis revealed that 29 proteins were highly expressed, and 25 proteins were less represented in the valve than endocardial endothelium. The first part of the study was already available in the ProteomeXchange Consortium (PXD009194).
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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:Autophagy-lysosomal degradation is an evolutionarily conserved process key to cellular homeostasis, differentiation, and stress survival, which is particularly important to the pathophysiology of the cardiovascular system. What is more, both experimental and clinical observations indicate that autophagy-lysosomal degradation affects correct cardiac morphogenesis, and in particular valve development. However, it is still unclear which cells upregulate autophagy-lysosomal degradation and for which specific cellular processes it is required. Here, we introduce novel zebrafish transgenic models to visualize autophagosomes and lysosomes in vivo and to follow their temporal and cellular localization in the larval heart. This allowed us to determine the kinetics of autophagosome and lysosome vesicle formation and to observe significant accumulation of lysosomal vesicles during the development of the atrioventricular and bulboventricular valves. We then addressed the functional role of lysosomal degradation in cardiovascular development using a spns1 mutant as a zebrafish model of lysosomal impairment. We found that spns1 mutants displayed morphologically and functionally abnormal heart development, including abnormal endocardial organization, impaired cardiac valve formation and high incidence of retrograde blood flow. Single-nuclear transcriptome analysis revealed endocardial-specific differences in the expression of lysosome-related genes and alterations of notch1 signaling in the mutant larval heart. Further, endocardial-specific overexpression of spns1 and notch1 rescued features of valve formation and function as well as overall cardiac morphogenesis. Altogether, our study provides an improved description of the autophagy and lysosomal events that take place during zebrafish heart development and reveals a cell-autonomous role of lysosomal processing during cardiac valve formation upstream of notch1 signaling.
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Project description:Gene expression profile of single endocardial cells in 48 and 72 hpf zebrafish embryos/larvae. In the study "The heart is a niche for hematopoietic stem and progenitor cells in zebrafish."
| PRJNA1121299 | ENA
Project description:Transcriptional profiling of zebrafish embryo comparing wild type untreated embryos with embryos injected with morpholino of zf-grna. This assay is used for determination of expression profiling of trunk muscle at 16, 24, 48, 72 hpf under GRN-A deficiency.
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Project description:One third of cardiac congenital diseases affect cardiac valves. Genetically modifiedmice have advancedourunderstandingof valve development and related pathologies. However, little is known with regard tohuman valve development.We aimed to derive a novel human pluripotent stem cellmodel in order to decode the early steps of human valvulogenesis.Human MesP1+mesodermal cells were differentiated toward the fate of second heart field progenitors and then to a selected population of pre-valvular endocardial cells. Gene arrays revealed that these human prevalvular cells (HPVC) express patterns of genes similar to those expressed in theatrioventricular canal (AVC) endocardium of E9.0 mouse embryos. In mice this developmental time precedes endocardial mesenchymal transition (EndoMT),which is required for mature valve formation.HPVC treated with BMP2, cultured onto chick or mouse AVC cushions, or transplanted into the outflow tract or AVC of embryonic chick and mouse hearts, underwent EndoMTin both a Notch-dependent and independent-manner and expressed markers of valve mesenchymal cells and fibroblasts.Similar to the previously described valve interstitial cells (VICs), HPVC also differentiate into tendinous/chondrogenic cells. Our study indicates thathuman pluripotent stem cells canrecapitulate early valvulogenesis and thus provide a powerful model to further decipher the origin and lineage contributionof different valvular cell typesin humans.
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