Cellular Landscapes of Nondiseased Human Cardiac Valves From End-Stage Heart Failure–Explanted Heart

Abstract

Background: Exploring the mechanisms of valvular heart disease at the cellular level may be useful to identify new therapeutic targets; however, the comprehensive cellular landscape of nondiseased human cardiac valve leaflets remains unclear. Methods: The cellular landscapes of nondiseased human cardiac valve leaflets (5 aortic valves, 5 pulmonary valves, 5 tricuspid valves, and 3 mitral valves) from end-stage heart failure patients undergoing heart transplantation were explored using single-cell RNA sequencing. Bioinformatics was used to identify the cell types, describe the cell functions, and investigate cellular developmental trajectories and interactions. Differences among the 4 types of cardiac valves at the cellular level were summarized. Pathological staining was performed to validate the key findings of single-cell RNA sequencing. An integrative analysis of our single-cell data and published genome-wide association study-based and bulk RNA sequencing-based data provided insights into the cell-specific contributions to calcific aortic valve diseases. Results: Six cell types were identified among 128 412 cells from nondiseased human cardiac valve leaflets. Valvular interstitial cells were the largest population, followed by myeloid cells, lymphocytes, valvular endothelial cells, mast cells, and myofibroblasts. The 4 types of cardiac valve had distinct cellular compositions. The intercellular communication analysis revealed that valvular interstitial cells were at the center of the communication network. The integrative analysis of our single-cell RNA sequencing data revealed key cellular subpopulations involved in the pathogenesis of calcific aortic valve diseases. Conclusions: The cellular landscape differed among the 4 types of nondiseased cardiac valve, which might explain their differences in susceptibility to pathological remodeling and valvular heart disease.

Network-Guided Multiomic Mapping of Aortic Valve Calcification

“…Although not directly focused on CAVD pathogenesis, the comparative study of distinct cellular compositions of 18 nondiseased human aortic, pulmonary, tricuspid, and mitral valves from end-stage heart failure patients has provided a baseline for valvular heterogeneity and shed light on left/right-side differences in leaflet composition, mechanobiological regulation of VIC phenotypes, and disease susceptibility of the AV. 39 Xu et al 15 reported the first scRNA-seq study of adult human CAVD, where they sequenced 34 632 cells from 6 donors after mechanical dissociation and enzymatic digestion. Their analyses identified subsets of VICs, VECs, macrophages, and lymphocytes.…”

A multimodal omics framework to empower target discovery for cardiovascular regeneration

“…These results could potentially explain important sex-differences in myocardial infarction observed in clinical practice 34 . Like the four chambers, the four cardiac valves were also shown to have distinct cellular composition: migratory valvular interstitial cells (VIC), mast cells, myo broblasts, and shear stress-reactive valvular endothelial cells (VEC) were found in aortic valve; shear stress-reactive VEC and mast cells were in pulmonary valve; nitric oxide (NO)-associated VIC, protective VEC, and migratory anti-in ammatory T cells were found in tricuspid vale; and mast cells and myo broblasts were in mitral valve 35 . Other specialised subdomains such as sinoatrial node (SAN) have also been studied at single cell level: a study of 718 SAN cells from 21 adult mice has identi ed Vsnl1 as a potential sinoatrial node marker and de ned four distinct transcriptional cluster 36 .…”

Integrated Pathogenesis of Vascular and Cardiac Valve Disease

“…Emerging studies at a single-cell level revealed molecular heterogeneity among valvular endothelial cells. [10][11][12][13] Importantly, these studies identified genes, such as transcription factor Prox1, marking diverse subpopulations within valvular endothelial cells lining cardiac valves. 13 These findings suggest Prox1, thought to be expressed specifically in lymphatic and venous valve endothelium, [14][15][16] as components of shared common pathways driving multisystem valvular defects.…”