Single-cell analysis reveals the loss of progenitor subpopulation of valvular endothelial cells leads to functional mitral regurgitation
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE241947 | GEO | 2024/12/27
REPOSITORIES: GEO
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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:Mitral valve leaflet response to ischemic mitral regurgitation: From gene expression to tissue remodeling
| PRJNA587626 | ENA
Project description:Regulatory Mechanisms of Atrial Remodeling of Human Mitral Regurgitation
2016-11-07 | GSE63045 | GEO
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:Mitral and tricuspid valves are essential for unidirectional blood flow in the heart. They are derived from similar cell sources, and yet congenital dysplasia affecting both valves is clinically rare, suggesting the presence of differential regulatory mechanisms underlying their development. We specifically inactivated Dicer1 in the endocardium during cardiogenesis and found that Dicer1-deletion caused congenital mitral valve stenosis and regurgitation, while it had no impact on other valves. We showed that hyperplastic mitral valves were caused by abnormal condensation and extracellular matrix (ECM) remodeling. Our single-cell RNA Sequencing analysis revealed impaired maturation of mesenchymal cells and abnormal expression of ECM genes in mutant mitral valves. Furthermore, expression of a set of miRNAs that target ECM genes was significantly lower in tricuspid valves compared to mitral valves, consistent with the idea that the miRNAs are differentially required for mitral and tricuspid valve development. We thus reveal miRNA-mediated gene regulation as a novel molecular mechanism that differentially regulates mitral and tricuspid valve development, thereby enhancing our understanding of the non-association of inborn mitral and tricuspid dysplasia observed clinically.
2022-08-19 | GSE207226 | GEO
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:Single-cell analysis reveals the loss of progenitor subpopulation of valvular endothelial cells leads to functional mitral regurgitation
| PRJNA1010799 | ENA
Project description:Aortic valve regurgitation (AR) imposes a severe volume overload to the left ventricle (LV) which results in dilation, eccentric hypertrophy and eventually loss of function. Little is known about the impact of AR on LV gene expression. We therefore conducted a gene expression profiling study in the LV of male Wistar rats with chronic (9 months) and severe AR. Five male Wistar rats had one or two aortic valve leaflets punctured with a catheter under echocardiographic guidance in order to induce severe regurgitation (>65% of blood regurgitating during diastole from the aorta to the left ventricle). Five additional rats were sham-operated. The animals were sacrificed 9 months after the procedure and their left ventricle collected for RNA extraction and microarray analysis.
2010-04-13 | E-GEOD-17050 | biostudies-arrayexpress
Project description:The mitral valve is a highly complex structure which regulates blood flow from the left atrium to the left ventricle (LV) avoiding a significant forward gradient during diastole or regurgitation during systole. The integrity of the mitral valve is also essential for the maintenance of normal LV size, geometry, and function. Significant advances in the comprehension of the biological, functional, and mechanical behavior of the mitral valve have recently been made. However, current knowledge of protein components in the normal human mitral valve is still limited and complicated by the low cellularity of this tissue and the presence of high abundant proteins from the extracellular matrix. We employed here an integrated proteomic approach to analyse the protein composition of the normal human mitral valve and reported confident identification of 422 proteins, some of which have not been previously described in this tissue. In particular, we described the ability of pre-MS separation technique based on liquid-phase IEF and SDS-PAGE to identify the largest number of proteins. These initial results provide a valuable basis for future studies aimed at analysing in depth the mitral valve protein composition and at investigating potential pathogenetic molecular mechanisms.
2016-08-18 | PXD004397 | Pride
Project description:Heart valve diseases, such as aortic valve stenosis (AS) and mitral valve regurgitation (MR), are leading causes of heart failure. However, myocardial proteome studies in AS and MR are extremely rare. We profiled the proteome of 75 human left ventricular myocardial biopsies (AS=41, MR=17, controls=17) and detected disease- and sex-specific protein expression alterations. Patients with AS, for example, showed higher abundance of fibrosis-related proteins and lower abundance of proteins related to energy metabolism and protein synthesis capacity with prominent sex differences. This might explain the higher amount of myocardial mass and fibrosis and lower systolic cardiac function especially observed in male AS in our cohort and might help to find specific proteins as treatment targets. Our work provides detailed insight into myocardial protein alterations in AS and MR and expands, in combination with clinical parameters, the understanding of cardiac remodeling in female and male patients, aiming to improve disease- and sex-specific therapy.
2022-12-13 | PXD023800 | Pride