Spatial transcriptomics reveals expression of novel genes during the remodelling of the embryonic human heart
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. Overall design: Spatial transcriptomics of 2 embryonic human hearts. Consecutive tissue sections were taken from each sample CS19 (5 sections) and CS16 (4 sections) CS = Carnegie stage.