The effects of epicardial-specific deletion of Sox9 on parietal mitral valve leaflet development
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE236187 | GEO | 2024/02/14
REPOSITORIES: GEO
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Project description:Congenital heart malformations include mitral valve defects, which remain largely unexplained. During embryogenesis, a restricted population of endocardial cells within the atrioventricular canal undergoes an endothelial-to-mesenchymal transition to give rise to mitral valvular cells. However, the identity and fate decisions of these progenitors as well as the behavior and distribution of their derivatives in valve leaflets remain unknown. We used single-cell RNA sequencing (scRNA-seq) of genetically labeled endocardial cells and microdissected mouse embryonic and postnatal mitral valves to characterize the developmental road. We defined the metabolic processes underlying the specification of the progenitors and their contributions to subtypes of valvular cells. Using retrospective multicolor clonal analysis, we describe specific modes of growth and behavior of endocardial cell-derived clones, which build up, in a proper manner, functional valve leaflets. Our data identify how both genetic and metabolic mechanisms specifically drive the fate of a subset of endocardial cells toward their distinct clonal contribution to the formation of the valve.
2023-12-02 | GSE230849 | GEO
Project description:Rationale: Ischemic mitral regurgitation (IMR) is frequently observed following myocardial infarction (MI) and is associated with higher mortality and poor clinical prognosis if left untreated. Accumulating evidence suggests that mitral valve (MV) leaflets actively remodel post-MI, yet the cellular mechanisms underlying these responses and how this affects tissue function remain largely unknown. Objective: We sought to elucidate MV remodeling post-MI at the tissue, cellular, and transcriptomic levels. Methods and Results: The mechanical behavior of ovine MV leaflets pre-MI and 8 weeks post-MI reveal a significant decrease in radial direction extensibility, which essentially eliminated the mechanical anisotropy typically observed in healthy MVs. Quantitative histology and ultrastructural assessment by transmission electron microscopy revealed altered leaflet composition and architecture at 8 weeks post-MI. Assessment of the MV interstitial cell (MVIC) nuclear aspect ratio, a metric of cellular deformation, revealed that MVICs were on average rounder following MI. RNA sequencing (RNA-seq) indicated that YAP-induced genes were elevated at 4 weeks post-MI and genes related to extracellular matrix organization were some of the most downregulated in sheep with IMR compared to sheep without IMR at 4 weeks post-MI. Additionally, RNA-seq revealed the possible recruitment of immune cells in this remodeling process due to the drastic elevation of CXCL9 and CLEC10A. Conclusions: This multiscale assessment revealed significant mechanical and microstructural changes due to MI. RNA-seq provided a baseline for global gene expression changes in response to MI with and without IMR and suggests YAP-induced mechanotransduction, altered expression of ECM-related genes, and recruitment of immune cells as mechanisms contributing to altered MV biomechanics post-MI. Conclusions: This multiscale assessment revealed significant mechanical and microstructural changes due to MI. RNA-seq provided a baseline for global gene expression changes in response to MI with and without IMR and suggests YAP-induced mechanotransduction, altered expression of ECM-related genes, and recruitment of immune cells as mechanisms contributing to altered MV biomechanics post-MI.
2020-05-06 | GSE139921 | GEO
Project description:Bicuspid aortic valve (BAV) is a common congenital cardiac anomaly, with an estimated incidence of 1-2%. It is responsible for the greatest burden of aortic valve disease in patients younger than 70 years in North America. We performed microRNA profiling in end-stage valve leaflets with BAV and TAV. Patients undergoing elective aortic valve replacement for aortic stenosis at St. Michael’s Hospital, University of Toronto, between June 2010 and June 2011 were enrolled. Aortic valve leaflets were obtained intraoperatively from patients with congenital bicuspid (BAV; N=10) and tricuspid aortic valves (TAV; N=10) at the time of valve replacement. Leaflets were flash frozen in liquid nitrogen. MiRNA was isolated using the miRNeasy kit (Qiagen, Hilden, Germany) according to the manufacturer`s instructions. For miRNA microarray analysis, total RNA was directly labeled with biotin and hybridized to the GenoExplorer microRNA human array containing 1583 human miRNA probes (Genosensor, Tempe, AZ) and the fluorescent signals were then scanned using a GenePix 4000b Biochip. The average of 3 mean fluorescence signal intensities for each miRNA probe was normalized to that for tRNAmet. Precursor miRNAs detected at 2-fold greater than background were considered to be expressed. Data were analyzed with GenePix 5.0 software, provided by GenoSensor Corp.
2011-06-24 | E-GEOD-30197 | biostudies-arrayexpress
Project description:Aim: Test the hypothesis that 5HT receptors (5HTRs) signaling contributes to MVP pathophysiology. Methods and results: MV RNA was used for microarray analysis of MVP patients versus control, highlighting genes that indicate the involvement of 5HTR pathways and extracellular matrix remodeling in MVP. These canine MVP leaflets (N=5/group) showed 5HTR2B upregulation. Conclusion: In humans, MVP is associated with an upregulation in 5HTR2B expression and increased 5HT receptor signaling in the leaflets. 5HTR signaling is involved not only in previously reported 5HTrelated valvulopathies, but it is also involved in the pathological remodeling of MVP.
2018-01-29 | GSE109744 | GEO
Project description:We have generated scRNA-seq data from embryonic day (E)10.5 and E12.5 atrioventricular canals (primitive heart valves) to assess cellular diversity during the distinct epithelial-to-mesenchymal transitions (EMTs) from endocardium and epicardium that guide the formation of valve mesenchyme. Alongside, wildtype atrioventricular canals, we generated scRNA-seq data from Sox9 conditional knockouts (Sox9fl/fl;Tie2-cre) to explore the role of SOX9 in EMT. Atrioventricular canals were microdissected from cardiac chambers and outflow tract, enriching for heart valve progenitor lineages.
2023-06-30 | E-MTAB-11795 | biostudies-arrayexpress
Project description:Bicuspid aortic valve (BAV) is a common congenital cardiac anomaly, with an estimated incidence of 1-2%. It is responsible for the greatest burden of aortic valve disease in patients younger than 70 years in North America. We performed microRNA profiling in end-stage valve leaflets with BAV and TAV.
2011-06-24 | GSE30197 | GEO
Project description: Not available
| S-EPMC8298853 | biostudies-literature
Project description:Rational: We previously reported evidence of endothelial to mesenchymal transition (EndMT) and fibrosis in mitral valve (MV) leaflets at two to six months post-myocardial infarction (MI) in sheep. The onset of these changes and the mechanism of their instigation are not known. Early modulation of EndMT and fibrosis in MV leaflets may limit the development of ischemic mitral regurgitation (IMR) and heart failure. H Objective: To test the hypothesis that circulating molecules present in plasma within days after MI incite EndMT and fibrotic processes in MV leaflets. Method and Results: Ovine MVs harvested 8-10 days after inferior MI (IMI) showed an increase in MV thickness by histology and onset of EndMT, shown by increased CD31/α-smooth muscle actin (α-SMA)+ cells in post-MI MV leaflets (10.5±6.9%) versus sham (2.6±4%). In vitro, post-MI plasma induced EndMT and pro-fibrotic markers and enhanced migration of primary mitral valve endothelial cells (VECs). In contrast, sham plasma did not, despite the presence of TGFβ2 at levels known to induce EndMT in VECs (2 ng/ml). Analysis of sham versus post-MI plasma using a cytokine array revealed a significant drop in the Wnt signaling antagonist secreted frizzled-related protein 3 (sFRP3) in post-MI plasma compared to sham plasma, which was confirmed by ELISA. Addition of recombinant sFRP3 to post-MI plasma reversed its EndMT-inducing effect on mitral VECs, measured by restored VE-cadherin, reduced α-SMA, and reduced TGFβ1-3 expression. Extracellular signal related kinase 1/2 and SMAD2/3 phosphorylation were increased in mitral VEC by post-MI plasma, and both were blocked by supplementing the post-MI plasma with sFRP3. RNA-seq analysis of mitral VECs exposed to post-MI versus sham plasma for 24 hours showed upregulated forkhead box M1 (FOXM1), a transcription factor previously shown to drive fibrosis. FOXM1 was co-localized with CD31 in MV leaflets obtained from sheep at 8-10 days post-MI, which suggests FOXM1 may be linked to EndMT initiation. Blocking FOXM1 with Siomycin A (Sio A) reduced EndMT and pro-fibrotic transcripts in post-MI plasma treated mitral VECs. Finally, post-MI plasma-induced and TGFβ-induced FOXM1 was downregulated by sFRP3. Conclusions: Reduced sFRP3 in post-MI plasma appears to facilitate the onset of TGFβ-driven EndMT and fibrosis in mitral VECs by increasing the transcription factor FOXM1. Restoring sFRP3 levels and/or inhibiting FOXM1 may provide new strategies to minimize maladaptive changes that occur in the MV due to MI.
2022-01-15 | GSE182696 | GEO
Project description: Not available
| S-EPMC6716313 | biostudies-literature
Project description:Valve remodeling is a complex process involving extracellular matrix organization, development of trilaminar structures, and physical elongation of valve leaflets. However, the cellular and molecular mechanisms regulating valve remodeling and their roles in congenital valve disorders remain poorly understood. Semilunar valves and atrioventricular valves from healthy and age-matched human fetal hearts with pulmonary stenosis (PS) were collected. Single-Cell RNA-sequencing (scRNA-seq) was performed to determine the transcriptomic landscape of multiple valvular cell subtypes in valve remodeling and disease. Spatial localization of newly-identified cell subtypes was determined via immunofluorescence and RNA in situ hybridization. The molecular mechanisms mediating valve development was investigated utilizing primary human fetal valve interstitial cells (VICs) and endothelial cells (VECs). scRNA-seq analysis of healthy human fetal valves identified a novel APOE+ elastin-producing VIC subtype (Elastin-VIC) spatially located underneath VECs sensing the unidirectional flow. Knockdown of APOE in fetal VICs resulted in significant elastogenesis defects. In pulmonary valve with PS, we observed decreased expression of APOE and other genes regulating elastogenesis such as EMILIN1 and LOXL1, as well as elastin fragmentation. These findings suggested the crucial role of APOE in regulating elastogenesis during valve remodeling. Furthermore, cell-cell interaction analysis revealed that JAG1 from unidirectional VECs activates NOTCH signaling in Elastin-VICs through NOTCH3. In vitro Jag1 treatment in VICs increased the expression of elastogenesis-related genes and enhanced contractile functions with related gene expression. This was accompanied by activation of NOTCH signaling and elastogenesis observed in VICs co-cultured with VECs in the presence of unidirectional flow. Notably, we found that the JAG1-NOTCH3 signaling pair was drastically reduced in the PS valves. Lastly, we demonstrated that APOE is indispensable for JAG1-induced NOTCH activation in VICs, reinforcing the presence of a synergistic intrinsic and external regulatory network involving APOE and NOTCH signaling that is responsible for regulating elastogenesis during human valve remodeling. scRNA-seq analysis of human fetal valves identified a novel Elastin-VIC subpopulation, and revealed mechanism of intrinsic APOE and external NOTCH signaling from VECs sensing unidirectional flow in regulating elastogenesis during valve remodeling. These mechanisms may contribute to the pathogenesis of elastic malformation in congenital valve disease.
2024-01-10 | GSE228638 | GEO