Ligand-Receptor Analysis of Brain Cell Type Marker Data Reveals Intricate Endothelial Interaction.

Abstract

Background: Brain endothelial interaction with neurons, astrocytes, oligodendrocytes and microglial cells is critical for brain physiology; it is still far from being mapped. Understanding of the endothelial communication with other brain cell type could unravel novel insight into neurovascular homeostasis.

Purpose: This study aims to construct neurovascular interaction network, focusing on brain endothelial cell interactome using brain cell marker gene dataset and ligand-receptor (LR) pair.

Methods: We curated brain marker gene list from McKenzie et al.'s brain cell type top 1000 marker list of endothelial, microglia, astrocyte, neuron, oligodendrocyte and oligodendrocyte progenitor cell (OPC) and extracted LR interaction between them. Subsequently, using Cytoscape, endothelial cell interaction map was constructed and top interaction and hub gene were derived. Moreover, we performed Kyoto encyclopedia of genes and genomes (KEGG) pathways enrichment (p value < .1) to infer biological information hidden.

Results: Neurovascular LR interaction showed endothelial cells as the top network having 25.34% of total interaction with 176 outgoing and 171 incoming interactions. A considerable portion of signalling (11%) is involved in autocrine signalling functionally related to vascular tone, angiogenesis and others. Paracrine signalling between endothelial cells with microglia, astrocytes, neurons and OPC constituted 13.5%, 8.9%, 5.8% and 4.9% of total interactions, respectively. Functional enrichment of LR interaction in endothelial-microglia, endothelial-astrocyte and endothelial-neuron networks constitutes 49, 45 and 36 significant KEGG pathways (p value < .1) respectively. These pathways include extracellular matrix (ECM) receptor, axon guidance, chemokine, nuclear factor kappa B (NF-kB) and signalling pathways, among others. Hub gene analysis showed ITGB1 in endothelial cells, ITGA4 in microglia, NOTCH2 in astrocytes and LAMC2 in neurons having maximum interaction in the endothelial network.

Conclusion: This study recapitulated not only previously known gene interactions using a markers gene list but also identified novel interactions between endothelial and other brain cell types. In conclusion, this analysis underscores the critical role of endothelial cell interactions in brain physiology.