Comparative analysis of cell-cell communication at single-cell resolution

Inference of cell-cell communication from single-cell RNA-sequencing data is a powerful technique to uncover intercellular communication pathways, yet existing methods perform this analysis at the level of the cell type or cluster, discarding single-cell level information. Here we present Scriabin, a flexible and scalable framework for comparative analysis of cell-cell communication at single-cell resolution that is performed without cell aggregation or downsampling. We use multiple published atlas-scale datasets, genetic perturbation screens, and direct experimental validation to show that Scriabin accurately recovers expected cell-cell communication edges and identifies communication networks that can be obscured by agglomerative methods. Additionally, we use spatial transcriptomic data to show that Scriabin can uncover spatial features of interaction from dissociated data alone. Finally, we demonstrate applications to longitudinal datasets to follow communication pathways operating between timepoints. Our approach represents a broadly applicable strategy to reveal the full structure of niche-phenotype relationships in health and disease. Peripheral blood mononuclear cells (PBMCs) were isolated from a single donor. NK cells and B cells were isolated from these PBMCs and mRNAs encoding either GFP, CD40, or CD40L were transfected via CARTs. NK and B cells were co-cultured and subjected to single-cell RNA sequencing via the Seq-Well platform.