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Spatial transcriptomics reveals expression of novel genes during the remodelling of the embryonic human heart

ABSTRACT: Congenital heart defects are very common, with around 2% of the population having a valve anomaly. During development of the heart, and specifically the heart valves, cells change from distinct undifferentiated populations of progenitors into specialized cells organized with precise spatial locations within complex tissue structures. Knowledge of both the spatial location and the transcriptional profile of the progenitors and differentiated cells is necessary to understand the differentiation process and the formation of the complex 3-dimensional architecture of the valves. Disruption to these processes leads to congenital valve defects and these are associated with significant morbidity (valve disease is the most common cause of cardiac surgery in the over-50s), particularly during aging. Here we utilized a spatial transcriptomic approach (Stahl et al, 2016; DeLaughter et al, 2016; Vickovic et al, 2019) to derive data about gene expression in the arterial valves of the human embryo, during the sculpting phases of their development. We identified a number of genes that have not been previously linked to valve development and are strongly expressed in the remodelling valve leaflets. Examination of the mouse model for one of these, RBP1, shows previously undescribed defects in the great arteries and valve anomalies in mutant animals, highlighting that these genes are good candidate genes for causing BAV. Thus, we have developed new methodologies for ST data analysis and show that they have the ability to identify previously unknown developmentally important genes. ST is thus an exciting tool for novel gene discovery in the developing human embryo.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244723 | GEO | 2023/10/27

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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Spatial transcriptomics reveals expression of novel genes during the remodelling of the embryonic human heart

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