Neural Crest-Derived Endocardial Cells Required for Heart Valve Development

Abnormalities in cardiac valves, which maintain unidirectional blood flow through the heart, affect 2-3% of people worldwide and are the most common form of structural heart disease (1).Yet the cell types that make up the valve, and how they communicate to direct development and homeostasis, remain poorly understood. Here, we identify a rare, essential population of highly secretory valve endocardial cells in mouse and human that derive from migrating neural crest cells. Ablation of these cells in mice caused perinatal lethality with thickened leaflets, stenosis, and regurgitation, mirroring human valve disease. This subset of endocardial cells uniquely expresses the secreted signaling protein parathyroid hormone-like hormone (Pthlh). Global disruption of Pthlh caused valve stenosis and lethality and neural crest-specific deletion produced similar valve disease, with impaired maturation of valvular interstitial cells and disrupted bone morphogenetic protein signaling. These findings identify a previously unrecognized cell type and signaling pathway essential for valve morphogenesis, with implications for the pathogenesis and treatment of human valve defects.