Squidiff: Predicting cellular development and responses to perturbations using a diffusion model

Abstract Single-cell sequencing has revolutionized our understanding of cellular heterogeneity and responses to environmental stimuli. However, mapping transcriptomic changes across diverse cell types in response to various stimuli and elucidating underlying disease mechanisms remains challenging. Studies involving physical stimuli, such as radiotherapy, or chemical stimuli, like drug testing, demand labor-intensive experimentation, hindering mechanistic insight and drug discovery. Here we present Squidiff, a diffusion model-based generative framework that predicts transcriptomic changes across diverse cell types in response to environmental changes. We demonstrate Squidiff’s robustness across cell differentiation, gene perturbation, and drug response prediction. Through continuous denoising and semantic feature integration, Squidiff learns transient cell states and predicts high-resolution transcriptomic landscapes over time and conditions. Furthermore, we applied Squidiff to model blood vessel organoid development and cellular responses to neutron irradiation and growth factors. Our results demonstrate that Squidiff enables in silico screening of molecular landscapes, facilitating rapid hypothesis generation and providing valuable insights for precision medicine.