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Multiple cell trypes, incluiding melanocytes, contribute to elastogenesis in the developing murine aortic valve

ABSTRACT: Elastic fibers are required for expansion and recoil during contraction and relaxation of vessels and heart valves. The aortic valve (AoV) extracellular matrix is generated and maintained by valvular interstitial cells (VICs), a heterogeneous population of cells derived from a mixture of developmental precursors such as endocardium, neural crest and second heart field. Although most studies have focused on VICs that exhibit a fibroblastic phenotype, significant subpopulations present with neuronal, glial, smooth muscle and melanocytic phenotypes. Relatively little is known about which sub population of VICs regulate and produce elastic fibers, though elastin (Eln) abnormalities result in congenital AoV defects and Eln degradation initiates AoV diseases. The present study establishes the timing ofElnexpression in the murine AoV. We performed RT-qPCR and found thatElnpeaks at late embryogenesis (embryonic day 17.5) and early postnatal (P) stages and decreases to low levels in adulthood. Using spatial transcriptomics in postnatal day 3 AoV, we segregated AoV cells from other cardiac cells and demonstrated thatElnexpression correlates with that of genes known to regulate elastogenesis, including the common smooth muscle cell marker - Acta2. By combining RNAscopein situhybridization with immunofluorescence, we confirmed that VICs that expressElnco-express alpha smooth muscle actin. Additionally, some of theEln/alpha smooth muscle actin expressing cells also express melanocytic markers. As previously reported in adult mice, we show a relationship between AoV pigment and elastic fiber patterning during early postnatal stages and further show that melanocytes may play a critical role in elastogenesis. Our results indicate that in the murine AoVElnis produced during early postnatal stages by cells that co-express phenotypic markers of various cell types, including smooth muscle actin and melanocytic specific genes.

ORGANISM(S): Mus musculus

PROVIDER: GSE254500 | GEO | 2024/10/30

REPOSITORIES: GEO

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Project description:Valve remodeling is a complex process involving extracellular matrix organization, development of trilaminar structures, and physical elongation of valve leaflets. However, the cellular and molecular mechanisms regulating valve remodeling and their roles in congenital valve disorders remain poorly understood. Semilunar valves and atrioventricular valves from healthy and age-matched human fetal hearts with pulmonary stenosis (PS) were collected. Single-Cell RNA-sequencing (scRNA-seq) was performed to determine the transcriptomic landscape of multiple valvular cell subtypes in valve remodeling and disease. Spatial localization of newly-identified cell subtypes was determined via immunofluorescence and RNA in situ hybridization. The molecular mechanisms mediating valve development was investigated utilizing primary human fetal valve interstitial cells (VICs) and endothelial cells (VECs). scRNA-seq analysis of healthy human fetal valves identified a novel APOE+ elastin-producing VIC subtype (Elastin-VIC) spatially located underneath VECs sensing the unidirectional flow. Knockdown of APOE in fetal VICs resulted in significant elastogenesis defects. In pulmonary valve with PS, we observed decreased expression of APOE and other genes regulating elastogenesis such as EMILIN1 and LOXL1, as well as elastin fragmentation. These findings suggested the crucial role of APOE in regulating elastogenesis during valve remodeling. Furthermore, cell-cell interaction analysis revealed that JAG1 from unidirectional VECs activates NOTCH signaling in Elastin-VICs through NOTCH3. In vitro Jag1 treatment in VICs increased the expression of elastogenesis-related genes and enhanced contractile functions with related gene expression. This was accompanied by activation of NOTCH signaling and elastogenesis observed in VICs co-cultured with VECs in the presence of unidirectional flow. Notably, we found that the JAG1-NOTCH3 signaling pair was drastically reduced in the PS valves. Lastly, we demonstrated that APOE is indispensable for JAG1-induced NOTCH activation in VICs, reinforcing the presence of a synergistic intrinsic and external regulatory network involving APOE and NOTCH signaling that is responsible for regulating elastogenesis during human valve remodeling. scRNA-seq analysis of human fetal valves identified a novel Elastin-VIC subpopulation, and revealed mechanism of intrinsic APOE and external NOTCH signaling from VECs sensing unidirectional flow in regulating elastogenesis during valve remodeling. These mechanisms may contribute to the pathogenesis of elastic malformation in congenital valve disease.

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Multiple cell trypes, incluiding melanocytes, contribute to elastogenesis in the developing murine aortic valve

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