High cardiomyocyte diversity in human early prenatal heart development

Abstract

Cardiomyocytes play key roles during cardiogenesis, but have poorly understood features, especially in prenatal stages. Thus, we have characterized human prenatal cardiomyocytes, 6.5–7 weeks post-conception, in detail by integrating single–cell RNA sequencing, spatial transcriptomics, and ligand–receptor interaction information. Using a computational workflow developed to dissect cell type heterogeneity, localize cell types, and explore their molecular interactions, we identified eight types of developing cardiomyocyte, more than double compared to the ones identified in the Human Developmental Cell Atlas. These have high variability in cell cycle activity, mitochondrial content, and connexin gene expression, and are differentially distributed in the ventricles, including outflow tract, and atria, including sinoatrial node. Moreover, cardiomyocyte ligand–receptor crosstalk is mainly with non–cardiomyocyte cell types, encompassing cardiogenesis-related pathways. Thus, early prenatal human cardiomyocytes are highly heterogeneous and develop unique location–dependent properties, with complex ligand–receptor crosstalk. Further elucidation of their developmental dynamics may give rise to new therapies.

De novo spatiotemporal modelling of cell-type signatures in the developmental human heart using graph convolutional neural networks

“…Despite the clear limitation of using a subset of markers for identifying clusters de novo , we have shown that leveraging deep learning representation power, spage2vec can also identify subpopulations through non-linear aggregation of spatial marker features, even without marker genes that can directly identify all cell populations. This is exemplified when comparing atrial and ventricular clusters described here with those reported in a follow up study by Sylvén et al [ 24 ] based on the combination of scRNA-seq and Spatial transcriptomics. They report two atrial clusters, trabecular and conduit atrium, that annotate to similar tissue distributions as spage2vec clusters pcw6-1-2 and pcw6-7.…”

“…For the ventricular clusters, similar principles prevail. Thus, Sylvén et al [ 24 ] report characteristics of compact, trabecular with subtypes, and Purkinje-related myocardium that have tissue distributions similar to spage2vec clusters pcw6-4,8,15 (see viewer) annotating outer and inner ventricular myocardium and thus with spage2vec based on concerted gene profiles. An exception is spage2vec cluster 24 with CDK1, NUSAP1 and TOP2A gene expressions that are highly specific for cardiomyoblasts with high fractions of cell cycle G2M and S phases and exosome-enriched gene expressions.…”