Robust identification of cell-cell communication heterogeneity in single cells

Communication between cells modulates cell fate decisions by relaying information across tissues and inducing intracellular responses mediated by gene regulatory networks. Inference of cell-cell communication from high throughput data such as single cell transcriptomics is gaining popularity due to the high data availability and ease to automate modeling over hundreds of signaling pathways. Studying how cell-cell communication operates across biological scales and influences cell fate decisions, however, remain a major open question. Here, we present scRICH, a framework and package that integrates mechanism-based, multiscale mathematical modeling with learning strategies to capture the complexity of cell-cell communication from single-cell and spatial transcriptomics data. scRICH unravels the heterogeneity of communication behavior within cell types, links cell-cell communication to cell fate decisions by incorporating dynamical information of RNA splicing, and connects the scales of cell-cell interactions and intracellular response by constructing multilayer regulatory networks. We validate scRICH with new experiments on EGF ligand/receptor co-expression in keratinocytes from skin-equivalent organoid, and compare these computational predictions against existing CCC inference methods. Applying scRICH to multiple biological scenarios demonstrate its ability to capture emerging relations between distinct cell-cell communication pathways, interactions at the onset of cell fate decision, and emerging trends in cell-cell communications along cell lineages and in space.