Naturally occurring combinations of receptors from single cell transcriptomics in endothelial cells

Domanskyi, Sergii; Hakansson, Alex; Meng, Michelle; Graff Zivin, Joshua S.; Piermarocchi, Carlo; Paternostro, Giovanni; Ferrara, Napoleone

VEGF inhibitor drugs have been successful, especially in ophthalmology, but not all patients respond to them. Combinations of drugs are likely to be needed for a really effective therapy of angiogenesis-related diseases. In this paper we describe naturally occurring combinations of receptors in endothelial cells that might help to identify targets for drug combinations. We also develop and share a new computational method and a software tool called DECNEO to identify them. Single-cell gene expression data are used to identify a set of co-expressed endothelial cell receptors, conserved among species (mice and human) and enriched, within a network, of connections to up-regulated genes. This set includes several receptors previously shown to play a role in angiogenesis. The reproducibility, evolutionary conservation and role in angiogenesis of the naturally occurring combinations of receptors are supported by multiple highly significant statistical tests from large datasets, including an independent validation set. We also show tissue-specific combinations and, in the case of choroid endothelial cells, consistency with both well-established and recent experimental findings, presented in a separate experimental paper. The results and methods presented here allow one small step forward in the understanding of the syntax of intercellular communication. AUTHOR SUMMARY Intercellular communication is essential for animal development and function and therefore it must have already been present when the first animals evolved, more than 600 million years ago. Many effective drugs act by modifying messages between cells. Thus, a fuller understanding of the language of cells should lead to the design of a wider range of safer, more effective drugs and drug combinations. In this paper we show an example of remarkable similarity in patterns of cellular communication between mice and humans, two species that began to diverge from their common ancestor approximately 75 million years ago. This paper focuses on combinations of signals important for the growth of blood vessels. The methods used, however, are of a general nature and take advantage of recent technology that is able to measure the quantities of molecules within a single cell. We hope that colleagues with expertise in different fields, science students, and people contemplating a career in science will be inspired by the prospect of one day fully understanding the ancient language of cells.