Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA274026 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Microarray gene expression profiling of the minimally cultured human heart valve interstitial and endothelial cells with and without treatment with BMP4 and TGFB3 signaling molecules
2018-01-29 | GSE65445 | GEO
Project description:Pulmonary valve stenosis (PVS) is the most common congenital heart defect in Noonan syndrome (NS) and related RASopathies, yet the molecular mechanisms that link the underlying pathogenic variants to the valve pathology remains poorly defined. Here, we utilized a human iPSC-based valve differentiation platform to generate the cardiac valve cell lineage—including fibrosa and spongiosa valve interstitial cell (VIC) subtypes. Applying this model to CRISPR-edited iPSCs carrying NS- and Noonan syndrome with multiple lentigines (NSML)-associated variants, we identified early mesodermal and endocardial specification defects in all lines. Additionally, we found that NS-iPSCs exhibited fibrosa VIC-specific defects in endothelial-to-mesenchymal transition (EndMT), which was most pronounced in PTPN11N308D (N308D) cells. Through single-cell transcriptomics, we revealed widespread dysregulation of extracellular matrix (ECM) programs in N308D fibrosa VICs, including increased expression of collagens and proteoglycans, as well as dysregulation of multiple genes involved in ECM remodeling. We also detected activation of RAS-MAPK, TGFb, and fibrosis-associated pathways in our transcriptional dataset. We then characterized the global signaling changes in N308D fibrosa VICs through mass spectrometry-based phosphoproteomic profiling, which identified coordinated increases in ERK, PKC, and stress-related kinases, as well as enhanced activity at the TGFb receptor. Functionally, we observed that N308D fibrosa VICs had an exaggerated upregulation of ECM genes in the presence of TGFb2 ligand, suggesting that these cells are hypersensitive to TGFb stimulation. Furthermore, we demonstrated that this pathological ECM-program occurs independently of BAMBI, a negative regulator of TGFb signaling that was found to be decreased in N308D fibrosa VICs. Lastly, we performed histopathological analyses of stenotic pulmonary valves from two NS infants, which demonstrated marked overproduction and disorganization of ECM, mirroring the findings from our iPSC-based disease model. Together, our data reveals a central mechanism where NS-associated alleles sensitize fibrosa VICs to TGFb, which leads to aberrant downstream TGFb signaling and drives the pathological ECM program in NS-associated PVS.
2026-03-06 | GSE315927 | 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:Expression analysis of human aortic valve interstitial cells (hAVICs), mitral valve interstitial cells(hMVICs) and dermal firbroblasts (hDFs)
| PRJNA175005 | ENA
Project description:Calcific aortic valve disease (CAVD) primarily involves osteogenic differentiation in human aortic valve interstitial cells (hVICs). Schisandrol B (SolB), a natural bioactive constituent, has known therapeutic effects on inflammatory and fibrotic disorders. However, its impact on valve calcification has not been reported. Transcriptome sequencing was used to analyze potential molecular pathways affected by SolB treatment. To explore the therapeutic mechanism of SolB, human valve interstitial cells were induced to undergo osteogenic differentiation by OM, with or without SolB treatment meanwhile. Among the signaling pathways enriched, the P53 signaling pathway was identified as the upstream regulator of other enriched pathways such as Cell cycle, Oocyte meiosis, Cytokine-cytokine receptor interactions. These pathways were regulated by the P53 signaling pathway and were reported to be stimulated by DNA damage, an early stage of pathological change in CAVD. The cytokine-cytokine receptor interaction signaling pathway was reported to correlate with calcified aortic valve disease. taken together, our data revealed potential therapitic mechanism p53 signaling of Schisandrol B treatment in hVICs calcification.
2024-04-29 | GSE265809 | GEO
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:Calcific aortic valve disease (CAVD) is a progressive disorder characterized by fibrosis, calcification, and endothelial dysfunction. Valvular interstitial cells (VICs) are the predominant cell type within the aortic valve and play key roles in valve remodeling. Recent evidence suggests that VICs exhibit phenotypic plasticity and may undergo mesenchymal-to-endothelial transition (MEndT) under calcific conditions. To explore the transcriptional landscape of this process, we performed RNA sequencing on primary porcine VICs cultured in growth medium (GM), osteogenic medium (OM) for 8 days, and primary porcine valve endothelial cells (pVECs). This dataset provides a resource for understanding the molecular mechanisms underlying MEndT and its potential contribution to CAVD pathogenesis.
2025-09-19 | GSE308127 | GEO
Project description:Stretch responsive miRNAs in human aortic valve interstitial cells
| PRJNA214242 | ENA
Project description:To explore the miR expression profile of calcified valve interstitial cells (VICs) induced by high calcium/phosphate, identify the key miRNA in the calcification process of VICs, and probe effect of miRs in regulating valve calcification.
2022-12-26 | GSE221671 | GEO