Understanding global communications among cells requires accurate representation of cell-cell signaling links and effective systems-level analyses of those links. We construct a database of interactions among ligands, receptors and their cofactors that accurately represent known heteromeric molecular complexes. We then develop CellChat, a tool that is able to quantitatively infer and analyze intercellular communication networks from single-cell RNA-sequencing (scRNA-seq) data. CellChat predicts major signaling inputs and outputs for cells and how those cells and signals coordinate for functions using network analysis and pattern recognition approaches. Through manifold learning and quantitative contrasts, CellChat classifies signaling pathways and delineates conserved and context-specific pathways across different datasets. Applying CellChat to mouse and human skin datasets shows its ability to extract complex signaling patterns. Our versatile and easy-to-use toolkit CellChat and a web-based Explorer (http://www.cellchat.org/) will help discover novel intercellular communications and build cell-cell communication atlases in diverse tissues.

DifferentialEquations.jl is a package for solving differential equations in Julia. It covers discrete equations (function maps, discrete stochastic (Gillespie/Markov) simulations), ordinary differential equations, stochastic differential equations, algebraic differential equations, delay differential equations, hybrid differential equations, jump diffusions, and (stochastic) partial differential equations. Through extensive use of multiple dispatch, metaprogramming, plot recipes, foreign function interfaces (FFI), and call-overloading, DifferentialEquations.jl offers a unified user interface to solve and analyze various forms of differential equations while not sacrificing features or performance. Many modern features are integrated into the solvers, such as allowing arbitrary user-defined number systems for high-precision and arithmetic with physical units, built-in multithreading and parallelism, and symbolic calculation of Jacobians. Integrated into the package is an algorithm testing and benchmarking suite to both ensure accuracy and serve as an easy way for researchers to develop and distribute their own methods. Together, these features build a highly extendable suite which is feature-rich and highly performant. Funding statement: This work was partially supported by NIH grants P50GM76516 and R01GM107264 and NSF grants DMS1562176 and DMS1161621. This material is based upon work supported by the National Science Foundation Graduate Research Fellowship under Grant No. DGE-1321846, the National Academies of Science, Engineering, and Medicine via the Ford Foundation, and the National Institutes of Health Award T32 EB009418. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH

Distinguishing biological from technical variation is crucial when integrating and comparing single-cell genomics datasets across different experiments. Existing methods lack the capability in explicitly distinguishing these two variations, often leading to the removal of both variations. Here, we present an integration method scMC to remove the technical variation while preserving the intrinsic biological variation. scMC learns biological variation via variance analysis to subtract technical variation inferred in an unsupervised manner. Application of scMC to both simulated and real datasets from single-cell RNA-seq and ATAC-seq experiments demonstrates its capability of detecting context-shared and context-specific biological signals via accurate alignment.

Spatial transcriptomic technologies and spatially annotated single-cell RNA sequencing datasets provide unprecedented opportunities to dissect cell–cell communication (CCC). However, incorporation of the spatial information and complex biochemical processes required in the reconstruction of CCC remains a major challenge. Here, we present COMMOT (COMMunication analysis by Optimal Transport) to infer CCC in spatial transcriptomics, which accounts for the competition between different ligand and receptor species as well as spatial distances between cells. A collective optimal transport method is developed to handle complex molecular interactions and spatial constraints. Furthermore, we introduce downstream analysis tools to infer spatial signaling directionality and genes regulated by signaling using machine learning models. We apply COMMOT to simulation data and eight spatial datasets acquired with five different technologies to show its effectiveness and robustness in identifying spatial CCC in data with varying spatial resolutions and gene coverages. Finally, COMMOT identifies new CCCs during skin morphogenesis in a case study of human epidermal development.

Single-cell RNA sequencing (scRNA-seq) provides details for individual cells; however, crucial spatial information is often lost. We present SpaOTsc, a method relying on structured optimal transport to recover spatial properties of scRNA-seq data by utilizing spatial measurements of a relatively small number of genes. A spatial metric for individual cells in scRNA-seq data is first established based on a map connecting it with the spatial measurements. The cell–cell communications are then obtained by “optimally transporting” signal senders to target signal receivers in space. Using partial information decomposition, we next compute the intercellular gene–gene information flow to estimate the spatial regulations between genes across cells. Four datasets are employed for cross-validation of spatial gene expression prediction and comparison to known cell–cell communications. SpaOTsc has broader applications, both in integrating non-spatial single-cell measurements with spatial data, and directly in spatial single-cell transcriptomics data to reconstruct spatial cellular dynamics in tissues.