Jiahe Qian

Yaoyu Fang, Jiahe Qian, Xinkun Wang et al.

Spatial Transcriptomics (ST) provides spatially resolved gene expression profiles within intact tissue architecture, enabling molecular analysis in histological context. However, the high cost, limited throughput, and restricted data sharing of ST experiments result in severe data scarcity, constraining the development of robust computational models. To address this limitation, we present a Central-to-Local adaptive generative diffusion framework for ST (C2L-ST) that integrates large-scale morphological priors with limited molecular guidance. A global central model is first pretrained on extensive histopathology datasets to learn transferable morphological representations, and institution-specific local models are then adapted through lightweight gene-conditioned modulation using a small number of paired image-gene spots. This strategy enables the synthesis of realistic and molecularly consistent histology patches under data-limited conditions. The generated images exhibit high visual and structural fidelity, reproduce cellular composition, and show strong embedding overlap with real data across multiple organs, reflecting both realism and diversity. When incorporated into downstream training, synthetic image-gene pairs improve gene expression prediction accuracy and spatial coherence, achieving performance comparable to real data while requiring only a fraction of sampled spots. C2L-ST provides a scalable and data-efficient framework for molecular-level data augmentation, offering a domain-adaptive and generalizable approach for integrating histology and transcriptomics in spatial biology and related fields.

Yaoyu Fang, Jiahe Qian, Xinkun Wang et al.

Spatial transcriptomics (ST) has revolutionized biomedical research by enabling high resolution gene expression profiling within tissues. However, the high cost and scarcity of high resolution ST data remain significant challenges. We present Single-shot Sparser-to-Sparse (S2S-ST), a novel framework for accurate ST imputation that requires only a single and low-cost sparsely sampled ST dataset alongside widely available natural images for co-training. Our approach integrates three key innovations: (1) a sparser-to-sparse self-supervised learning strategy that leverages intrinsic spatial patterns in ST data, (2) cross-domain co-learning with natural images to enhance feature representation, and (3) a Cascaded Data Consistent Imputation Network (CDCIN) that iteratively refines predictions while preserving sampled gene data fidelity. Extensive experiments on diverse tissue types, including breast cancer, liver, and lymphoid tissue, demonstrate that our method outperforms state-of-the-art approaches in imputation accuracy. By enabling robust ST reconstruction from sparse inputs, our framework significantly reduces reliance on costly high resolution data, facilitating potential broader adoption in biomedical research and clinical applications.

Ziqiao Weng, Yaoyu Fang, Jiahe Qian et al.

Spatial transcriptomics (ST) bridges gene expression and tissue morphology but faces clinical adoption barriers due to technical complexity and prohibitive costs. While computational methods predict gene expression from H&E-stained whole-slide images (WSIs), existing approaches often fail to capture the intricate biological heterogeneity within spots and are susceptible to morphological noise when integrating contextual information from surrounding tissue. To overcome these limitations, we propose HiFusion, a novel deep learning framework that integrates two complementary components. First, we introduce the Hierarchical Intra-Spot Modeling module that extracts fine-grained morphological representations through multi-resolution sub-patch decomposition, guided by a feature alignment loss to ensure semantic consistency across scales. Concurrently, we present the Context-aware Cross-scale Fusion module, which employs cross-attention to selectively incorporate biologically relevant regional context, thereby enhancing representational capacity. This architecture enables comprehensive modeling of both cellular-level features and tissue microenvironmental cues, which are essential for accurate gene expression prediction. Extensive experiments on two benchmark ST datasets demonstrate that HiFusion achieves state-of-the-art performance across both 2D slide-wise cross-validation and more challenging 3D sample-specific scenarios. These results underscore HiFusion's potential as a robust, accurate, and scalable solution for ST inference from routine histopathology.

Jiahe Qian, Yaoyu Fang, Ziqiao Weng et al.

Spatial transcriptomics aims to connect high-resolution histology images with spatially resolved gene expression. To achieve better performance on downstream tasks such as gene expression prediction, large-scale pre-training is required to obtain generalisable representations that can bridge histology and transcriptomics across tissues, protocols, and laboratories. Existing cross-modal pre-training approaches for spatial transcriptomics rely on either gene names or expression values in isolation, which strips the gene branch of essential semantics and breaks the association between each gene and its quantitative magnitude. In addition, by restricting supervision to image-text alignment, these methods ignore intrinsic visual cues that are critical for learning robust image features. We present CoMTIP, the first Contrastive Masked Text-Image Pretraining framework that jointly learns from images, gene names, and expression values while capturing fine-grained visual context for spatial transcriptomics. The vision branch uses Masked Feature Modeling to reconstruct occluded patches and learn context-aware image embeddings. The text branch applies a scalable Gene-Text Encoder that processes all gene sentences in parallel, enriches each gene and its numerical value with dedicated embeddings, and employs Pair-aware Adversarial Training (PAAT) to preserve correct gene-value associations. Image and text representations are aligned in a shared InfoNCE-optimised space. Experiments on public spatial transcriptomics datasets show that CoMTIP not only surpasses previous methods on diverse downstream tasks but also achieves zero-shot gene expression prediction, a capability that existing approaches do not provide.