Cross-Species Multi-Omics Profiling Identifies Conserved Activated Valvular Interstitial Cell Population Driving Myxomatous Mitral Valve Degeneration
Year: 2026
Type: preprint
Abstract: Background: Primary mitral regurgitation resulting from mitral valve prolapse can lead to life-threatening complications, including arrhythmias, heart failure, and sudden cardiac death. Mitral valve prolapse is classically associated with myxomatous mitral valve degeneration, characterized by leaflet thickening, extracellular matrix disorganization, and progressive structural remodeling. Valvular interstitial cells, the predominant stromal population within the valve, maintain extracellular matrix homeostasis; however, their molecular heterogeneity, and state-specific contributions to disease pathogenesis remain incompletely defined. Methods: Using a fibrillin-1 deficient mouse model and human tissue specimens we integrated single-cell RNA sequencing with spatial transcriptomic profiling to construct a comprehensive atlas of cellular composition and extracellular matrix organization across normal mitral valves, sporadic mitral valve prolapse, and Marfan syndrome-associated mitral valve prolapse. Results: Analyses revealed spatially organized cellular niches and substantial heterogeneity within the valvular interstitial cell population. Across murine and human datasets, we identified a conserved activated valvular interstitial cell population enriched for profibrotic extracellular matrix remodeling programs and preferentially localized to mechanically vulnerable leaflet tip regions. This population exhibited coordinated upregulation of collagen- and matrix-associated genes, metabolic signatures consistent with enhanced mitochondrial activity, and transcriptional features suggesting fibro-inflammatory signaling. Conclusions: We identified a transcriptionally and spatially distinct activated valvular interstitial cell state conserved across species and disease etiologies that is strongly implicated in fibrotic remodeling during myxomatous mitral valve degeneration and provides a candidate therapeutic target.
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: High-spatial-resolution ECM-inclusive multi-omics sequencing of human PFA and FFPE tissue slides, High-spatial-resolution ECM-inclusive multi-omics sequencing of human PFA and FFPE tissue slides, Unraveling molecular Complexity of Mitral Valve Disease using single cell and Spatial Multi-Omics analysis", Yale TMC for Cellular Senescence in Lymphoid Organs, Yale Murine-TMC on Immune Cell Senescence Derived Inflammation
OpenAlex ID: W7140495065