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- W4380769096 abstract "Background: Semilunar and atrioventricular valves have distinct structures and are often affected differently in congenital valve diseases (CVD). Here we aim to define and compare the cellular composition and transcriptomic signatures of four different human fetal valves, which provide a reference map to engineer valves in vitro , and to study valve-specific impairment in CVD. Methods: Aortic, pulmonary, mitral, and tricuspid valves were barcoded respectively from a healthy human fetal heart at gestational day 105. Single-cell (sc)RNA-seq was performed. Spatial localization of new subpopulations was determined by immunostaining and in situ hybridization. Cell-cell interaction was revealed by cell-chat. Results: scRNA-seq analysis revealed major cell types including endothelial (VECs), interstitial (VICs), and immune cells. In addition to reported collagen & glycosaminoglycan (GAG) VIC in mice, VIC sub-clustering identified two human-specific APOE+ and CLDN11+ subpopulations. APOE+ VICs specifically located underneath VECs facing unidirectional flow, indicating cell-cell interaction of APOE+ VICs & VECs. VEC sub-clustering identified lymphatic VECs under turbulent flow, while CD55+ & PTGDS+ VECs under unidirectional flow. Cell-chat uncovered NOTCH3-JAG1 pairs in facilitating the co-development of spatially adjacent APOE+ VICs & PTGDS+ VECs. To further uncover valve-specific signatures, we compared gene expression profiles of four valves. In lymphatic VECs, genes regulating BMP pathway were enriched in semilunar valves. In GAG VICs, MAPK pathway was specifically enriched in pulmonary valve, indicating development of different valves may need activation of different pathways. Interestingly, when comparing valve with pulmonary atresia versus healthy pulmonary valve using scRNA-seq, both MAPK related genes and GAG VICs were significantly reduced, suggesting impaired MAPK may contribute to pulmonary-specific loss of GAG VICs leading to its abnormal development. Conclusion: Our high-resolution atlas of human fetal valves revealed subtypes of VIC & VEC with unique spatial locations. Comparison of four valves identified pulmonary valve-specific MAPK pathway that may explain loss of GAG VICs in patients with pulmonary atresia." @default.
- W4380769096 created "2023-06-16" @default.
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- W4380769096 date "2022-11-08" @default.
- W4380769096 modified "2023-10-16" @default.
- W4380769096 title "Abstract 9555: Human Valve Atlas in Health and Disease" @default.
- W4380769096 doi "https://doi.org/10.1161/circ.146.suppl_1.9555" @default.
- W4380769096 hasPublicationYear "2022" @default.
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