Diffusion Generative Modeling for Spatially Resolved Gene Expression Inference from Histology Images

Spatial Transcriptomics (ST) allows a high-resolution measurement of RNA sequence abundance by systematically connecting cell morphology depicted in Hematoxylin and Eosin (H&E) stained histology images to spatially resolved gene expressions. ST is a time-consuming, expensive yet powerful experimental technique that provides new opportunities to understand cancer mechanisms at a fine-grained molecular level, which is critical for uncovering new approaches for disease diagnosis and treatments. Here, we present $\textbf{Stem}$ ($\textbf{S}$pa$\textbf{T}$ially resolved gene $\textbf{E}$xpression inference with diffusion $\textbf{M}$odel), a novel computational tool that leverages a conditional diffusion generative model to enable in silico gene expression inference from H&E stained images. Through better capturing the inherent stochasticity and heterogeneity in ST data, $\textbf{Stem}$ achieves state-of-the-art performance on spatial gene expression prediction and generates biologically meaningful gene profiles for new H&E stained images at test time. We evaluate the proposed algorithm on datasets with various tissue sources and sequencing platforms, where it demonstrates clear improvement over existing approaches. $\textbf{Stem}$ generates high-fidelity gene expression predictions that share similar gene variation levels as ground truth data, suggesting that our method preserves the underlying biological heterogeneity. Our proposed pipeline opens up the possibility of analyzing existing, easily accessible H&E stained histology images from a genomics point of view without physically performing gene expression profiling and empowers potential biological discovery from H&E stained histology images.

Cell Spatial Analysis in Crohn's Disease: Unveiling Local Cell Arrangement Pattern with Graph-based Signatures

Crohn's disease (CD) is a chronic and relapsing inflammatory condition that affects segments of the gastrointestinal tract. CD activity is determined by histological findings, particularly the density of neutrophils observed on Hematoxylin and Eosin stains (H&E) imaging. However, understanding the broader morphometry and local cell arrangement beyond cell counting and tissue morphology remains challenging. To address this, we characterize six distinct cell types from H&E images and develop a novel approach for the local spatial signature of each cell. Specifically, we create a 10-cell neighborhood matrix, representing neighboring cell arrangements for each individual cell. Utilizing t-SNE for non-linear spatial projection in scatter-plot and Kernel Density Estimation contour-plot formats, our study examines patterns of differences in the cellular environment associated with the odds ratio of spatial patterns between active CD and control groups. This analysis is based on data collected at the two research institutes. The findings reveal heterogeneous nearest-neighbor patterns, signifying distinct tendencies of cell clustering, with a particular focus on the rectum region. These variations underscore the impact of data heterogeneity on cell spatial arrangements in CD patients. Moreover, the spatial distribution disparities between the two research sites highlight the significance of collaborative efforts among healthcare organizations. All research analysis pipeline tools are available at https://github.com/MASILab/cellNN.