Neurovascular Unit Interactome Analysis Identifying Astrocytic LRP1 as a key node in Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is particularly challenging to treat due to its complex nature and the initiation of complex pathogenic pathways. It is crucial to understand the series of events that might lead to subsequent brain injury in TBI. In order to identify frequent and important cellular interactions, we used previously published single-cell sequencing data (GSE89866 and GSE101901) from both animal and human TBI patient data to uncover common and significant cellular interaction. We created neurovascular unit (NVU) consisting of astrocytes, pericytes, neurons, endothelial cells and microglia cellular network using ligand receptor (LR) interaction. We used the newly curated LR pairings list to map ligand-receptor pairs between different NVU cell types in order to build this intracellular network. This LR interaction is visualised through Cytoscape, while intercellular interactions were depicted by Circos plots. Functional enrichment assessment was conducted utilizing DAVID Bioinformatics Resources to find significant Gene Ontology terms and KEGG pathways related to these connections. Our investigation revealed 69 ligands, 59 receptors and 128 LR interactions, demonstrating substantial intercellular communication across all cell types in brain. Astrocytes emerge as the most important interactome partners, with highest interaction density (~49%) with prominent autocrine and paracrine signalling roles. Network analysis showed astrocytic LRP1 as a central signalling hub interacting with several ligands, also common with human (GSE101901) dataset. It indicates its crucial function in regulating neurovascular responses after TBI. Overall, this study offers a systems-level framework of NVU interaction and highlights astrocyte-specific LRP1 as a possible therapeutic target for modifying neurovascular dysfunction following TBI. Multiple astrocyte pathways such as astrocyte-astrocyte, astrocyte-neuron, astrocyte-microglia were significantly enriched that are associated in TBI pathogenesis.