C3-Diff: Super-resolving Spatial Transcriptomics via Cross-modal Cross-content Contrastive Diffusion Modelling

The rapid advancement of spatial transcriptomics (ST), i.e., spatial gene expressions, has made it possible to measure gene expression within original tissue, enabling us to discover molecular mechanisms. However, current ST platforms frequently suffer from low resolution, limiting the in-depth understanding of spatial gene expression. Super-resolution approaches promise to enhance ST maps by integrating histology images with gene expressions of profiled tissue spots. However, it remains a challenge to model the interactions between histology images and gene expressions for effective ST enhancement. This study presents a cross-modal cross-content contrastive diffusion framework, called C3-Diff, for ST enhancement with histology images as guidance. In C3-Diff, we firstly analyze the deficiency of traditional contrastive learning paradigm, which is then refined to extract both modal-invariant and content-invariant features of ST maps and histology images. Further, to overcome the problem of low sequencing sensitivity in ST maps, we perform nosing-based information augmentation on the surface of feature unit hypersphere. Finally, we propose a dynamic cross-modal imputation-based training strategy to mitigate ST data scarcity. We tested C3-Diff by benchmarking its performance on four public datasets, where it achieves significant improvements over competing methods. Moreover, we evaluate C3-Diff on downstream tasks of cell type localization, gene expression correlation and single-cell-level gene expression prediction, promoting AI-enhanced biotechnology for biomedical research and clinical applications. Codes are available at https://github.com/XiaofeiWang2018/C3-Diff.