Analysis of cell–cell communication by single-nuclei RNA sequencing

Communication between cells is essential in maintaining homeostasis. The persistent disruption of cell–cell communication by environmental contaminants contributes to progressive disease and toxicity. In this study, researchers from Michigan State University used single-nuclei RNA sequencing (snRNAseq) data to examine dose-dependent cell-specific changes in cell–cell communication associated with the development of liver pathologies following the persistent activation of the aryl hydrocarbon receptor (AHR) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Published hepatic snRNAseq data from male mice gavaged with sesame-oil vehicle or TCDD every 4 days for 28 days was used to assess the AHR-mediated disruption of ligand–receptor interactions. Analysis identified that portal fibroblasts and liver sinusoidal endothelial cells contributed the most ligand–receptor pairs at doses < 0.3μg/kg TCDD. Doses ≥ 0.3 μg/kg TCDD increased the putative intercellular communication between hepatocytes and hepatic stellate cells. In control livers, interactions primarily consisted of protease-activated receptor (PAR) signaling. TCDD treatment increased the number of active signaling pathways. Within hepatocytes, neuregulin signaling was induced, activating the NRG1–ERBB4 ligand axis, consistent with AHR genomic enrichment at dioxin response elements in a published chromatin immunoprecipitation sequencing (ChIP-seq) dataset, which suggested a direct regulation. Collectively, the results suggest that the disruption of cell signaling may play a central role in TCDD-elicited liver pathologies.

Inferred cell–cell interactions

CellChat was used to infer ligand–receptor interactions using hepatic snRNAseq data (GSE184506, SCP1871) male mice gavaged with sesame-oil vehicle or 0.01–30 μg/kg TCDD every 4 days for 28 days. (a) The number and (b) strength, a measure of significance based on ligand, mediator, and receptor expression, are summarized across all cell types in the dataset. (c) Networks of cell–cell inferred interactions show the number of ligand–receptor pairs (edges) between each cell type (nodes) across treatment groups. The width of the edge indicates the number of ligand–receptor interactions between cell types. PFs—portal fibroblasts; pDCs—plasmacytoid dendritic cells; LSECS—liver sinusoidal endothelial cells; HSC—hepatic stellate cells.