SINGLE CELL MULTIOMICS REVEAL NOVEL CARDIAC SUBPOPULATION CRITICAL TO VALVE MORPHOGENESIS
Alexander F. Merriman, MS1, Peter Kouretas, MD, PhD2, Mauro Costa, PhD1, Chun J. Ye, PhD2, Deepak Srivastava, MD1.
1Gladstone Institutes, San Francisco, CA, USA, 2University of California, San Francisco, San Francisco, CA, USA.
Objective(s): Valvular heart disease is a major source of morbidity and mortality with an anticipated increase in prevalence secondary to an aging population and increase in survivorship for patients with congenital disease. Further developmental studies are required to advance novel therapeutic development such as tissue engineered heart valves.
Methods: In this study, we have interrogated the later stages of valvulogenesis to understand the molecular mechanisms of valve formation via single-cell RNA/Chromatin Accessibility sequencing in the developing mouse heart.
Results: We identified a novel, rare cell population in the developing valve with a unique transcriptional profile comprised of highly specific developmental signaling pathway genes. These cells are first detectable after valve primordia formation at embryonic day (E) 12.5 and are spatially localized at the leading edge of the developing leaflets. Ablation of this rare subpopulation during development results in highly dysplastic valves, characterized by hyperplastic, redundant, immature leaflets associated with valvular stenosis and regurgitation. These dysplastic features are consistent with the features of several congenital valvulopathies including Ebstein's Anomaly, and pulmonary or aortic valve stenosis. Single-cell RNA sequencing analysis of a human fetal heart with hypoplastic left heart syndrome and critical aortic stenosis demonstrated a depletion of this cell population in the diseased aortic valve, suggesting these cells may be required for normal human valvular development as well.
Conclusions: This study establishes the existence of a novel, rare subpopulation of cardiac cells that are critical to valve development and may contribute to the pathogenesis of congenital valvulopathies.
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