Spinster homolog 1 (spns1)-dependent endocardial autophagy-lysosomal pathway drives valve morphogenesis through the control of Notch1 signaling.
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PROVIDER: PRJNA1034995 | ENA |
REPOSITORIES: ENA
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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.
2024-10-25 | GSE246850 | 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.
2015-07-16 | GSE67786 | GEO
Project description:Aortic valve calcification is the most common form of valvular heart disease, but the mechanisms of calcific aortic valve disease (CAVD) are unknown. NOTCH1 mutations are associated with aortic valve malformations and adult-onset calcification in families with inherited disease. The Notch signaling pathway is critical for multiple cell differentiation processes, but its role in the development of CAVD is not well understood. The aim of this study was to investigate the molecular changes that occur with inhibition of Notch signaling in the aortic valve. Notch signaling pathway members are expressed in adult aortic valve cusps, and examination of diseased human aortic valves revealed decreased expression of NOTCH1 in areas of calcium deposition. To identify downstream mediators of Notch1, we examined gene expression changes that occur with chemical inhibition of Notch signaling in rat aortic valve interstitial cells (AVICs). We found significant downregulation of Sox9 along with several cartilage-specific genes that were direct targets of the transcription factor, Sox9. Loss of expression Sox9 has been published to be associated with aortic valve calcification. Utilizing an in vitro porcine aortic valve calcification model system, inhibition of Notch activity resulted in accelerated calcification while stimulation of Notch signaling attenuated the calcific process. Finally, the addition of Sox9 was able to prevent the calcification of porcine AVICs that occurs with Notch inhibition. In conclusion, loss of Notch signaling contributes to aortic valve calcification via a Sox9-dependent mechanism. 3 samples of aortic valve interstitial cells treated with DAPT were compared with 3 samples of aortic valve interstitial cells treated with DMSO
2011-08-25 | E-GEOD-31668 | biostudies-arrayexpress
Project description:Aortic valve calcification is the most common form of valvular heart disease, but the mechanisms of calcific aortic valve disease (CAVD) are unknown. NOTCH1 mutations are associated with aortic valve malformations and adult-onset calcification in families with inherited disease. The Notch signaling pathway is critical for multiple cell differentiation processes, but its role in the development of CAVD is not well understood. The aim of this study was to investigate the molecular changes that occur with inhibition of Notch signaling in the aortic valve. Notch signaling pathway members are expressed in adult aortic valve cusps, and examination of diseased human aortic valves revealed decreased expression of NOTCH1 in areas of calcium deposition. To identify downstream mediators of Notch1, we examined gene expression changes that occur with chemical inhibition of Notch signaling in rat aortic valve interstitial cells (AVICs). We found significant downregulation of Sox9 along with several cartilage-specific genes that were direct targets of the transcription factor, Sox9. Loss of expression Sox9 has been published to be associated with aortic valve calcification. Utilizing an in vitro porcine aortic valve calcification model system, inhibition of Notch activity resulted in accelerated calcification while stimulation of Notch signaling attenuated the calcific process. Finally, the addition of Sox9 was able to prevent the calcification of porcine AVICs that occurs with Notch inhibition. In conclusion, loss of Notch signaling contributes to aortic valve calcification via a Sox9-dependent mechanism.
2011-08-26 | GSE31668 | GEO
Project description:We are interested in the role of NOTCH1 and Shear Stress in Aortic Valve Endothelium. Primary human aortic valve endothelium was subjected to 4 conditions in vitro. 1) Control siRNA, No shear stress. 2) NOTCH1 siRNA, No shear stress. 3) Control siRNA, 15 dynes/cm2 shear stress. 4) NOTCH1 siRNA, 15 dynes/cm2 shear stress. Triplicates of each condition were pooled for library perp and sequencing
2015-05-16 | E-GEOD-47157 | biostudies-arrayexpress
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:We are interested in the role of NOTCH1 and Shear Stress in Aortic Valve Endothelium.
2015-05-16 | GSE47157 | GEO
Project description:We are interested in the role of NOTCH1 and Shear Stress in Aortic Valve Endothelium.
2015-05-16 | GSE47152 | GEO
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).
2022-02-17 | PXD025922 | Pride
Project description:We used single-cell RNA expression to uncover the cellular and molecular heterogeneity of isolated endocardial cells in the heart. From this study, we uncovered the presence of an endocardial-hematopoietic cluster, along with other significant clusters including valve endocardial and interstitial cells, and non-valve cells.
2024-07-31 | GSE269378 | GEO