SpotDiff: Spatial Gene Expression Imputation Diffusion with Single-Cell RNA Sequencing Data Integration

The advent of Spatial Transcriptomics (ST) has revolutionized understanding of tissue architecture by creating high-resolution maps of gene expression patterns. However, the low capture rate of ST leads to significant sparsity. The aim of imputation is to recover biological signals by imputing the dropouts in ST data to approximate the true expression values. In this paper, we introduce a Spatial Gene Expression Imputation Diffusion model to facilitate ST data imputation, and our model is referred to as SpotDiff. Specifically, we incorporate a spot-gene prompt learning module to capture the association between spots and genes. Further, SpotDiff integrates single-cell RNA sequencing data to impute gene expression at each spot. The proposed approach is able to reduce the uncertainty in the imputation process, since the aggregation of multiple single-cell measurements yield a stable representation of the corresponding spot expression profile. Extensive experiments have been performed to demonstrate that SpotDiff outperforms existing imputation methods across multiple benchmarks in terms of yielding more accurate and biologically relevant gene expression profiles, particularly in highly sparse scenarios. © 2025, Association for the Advancement of Artificial Intelligence (www.aaai.org). All rights reserved.