CoLa-VAE: A Cell–Cell Communication-Aware Variational Autoencoder for Representation Learning and Expression Denoising

Abstract Single-cell RNA sequencing provides a powerful view of cellular heterogeneity, but its sparsity and dropout noise remain major obstacles for recovering biologically meaningful gene expression programs and for downstream analyses that depend on reliable expression measurements. Ligand–receptor-based cell–cell communication inference is such analysis, missing ligand or receptor expression can cause substantial false negatives in sparse single-cell data. Here, we present CoLa-VAE, a cell–cell communication-aware variational autoencoder that jointly learns latent representations and denoised expression profiles by incorporating ligand–receptor-derived communication topology through dynamic graph Laplacian regularization. Rather than treating denoising as a secondary output of representation learning, CoLa-VAE uses denoised expression to iteratively refine communication estimates and uses the resulting communication structure to guide both latent organization and expression reconstruction. In addition to improving latent space organization and producing robust denoised expression matrices, CoLa-VAE-denoised matrices also improved downstream biological analyses, including the detection of robust differential cell–cell communication programs, mitigation of batch-associated variation and enhanced spatial transcriptomic deconvolution when spatially constrained communication structure was incorporated. Together, these results establish CoLa-VAE as a communication-guided denoising and representation learning framework that recovers biologically meaningful expression signals from sparse single-cell and spatial transcriptomic data, enabling more sensitive and reliable downstream analysis.