Chao Li

Xiaofei Wang, Stephen Price, Chao Li

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.

Xiaofei Wang, Xingxu Huang, Stephen J. Price et al.

The recent advancement of spatial transcriptomics (ST) allows to characterize spatial gene expression within tissue for discovery research. However, current ST platforms suffer from low resolution, hindering 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, current super-resolution methods are limited by restoration uncertainty and mode collapse. Although diffusion models have shown promise in capturing complex interactions between multi-modal conditions, it remains a challenge to integrate histology images and gene expression for super-resolved ST maps. This paper proposes a cross-modal conditional diffusion model for super-resolving ST maps with the guidance of histology images. Specifically, we design a multi-modal disentangling network with cross-modal adaptive modulation to utilize complementary information from histology images and spatial gene expression. Moreover, we propose a dynamic cross-attention modelling strategy to extract hierarchical cell-to-tissue information from histology images. Lastly, we propose a co-expression-based gene-correlation graph network to model the co-expression relationship of multiple genes. Experiments show that our method outperforms other state-of-the-art methods in ST super-resolution on three public datasets.

Xuepeng Liu, Zheng Jiang, Pinan Zhu et al.

Spatial transcriptomics (ST) reveals spatial heterogeneity of gene expression, yet its resolution is limited by current platforms. Recent methods enhance resolution via H&E-stained histology, but three major challenges persist: (1) isolating expression-relevant features from visually complex H&E images; (2) achieving spatially precise multimodal alignment in diffusion-based frameworks; and (3) modeling gene-specific variation across expression channels. We propose HaDM-ST (Histology-assisted Differential Modeling for ST Generation), a high-resolution ST generation framework conditioned on H&E images and low-resolution ST. HaDM-ST includes: (i) a semantic distillation network to extract predictive cues from H&E; (ii) a spatial alignment module enforcing pixel-wise correspondence with low-resolution ST; and (iii) a channel-aware adversarial learner for fine-grained gene-level modeling. Experiments on 200 genes across diverse tissues and species show HaDM-ST consistently outperforms prior methods, enhancing spatial fidelity and gene-level coherence in high-resolution ST predictions.