3D-Guided Scalable Flow Matching for Generating Volumetric Tissue Spatial Transcriptomics from Serial Histology

원문 초록

A 3D transcriptomic profile of a tissue can give a holistic view of its organization in health and disease, but spatial transcriptomics (ST) is costly, so usually only some serial sections are profiled, while H&E is available for all. Most methods that infer ST from histology treat each section independently and ignore 3D structure, while existing 3D-aware approaches are not generative and do not scale well. We present Holographic Tissue Expression Inpainting and Analysis (HoloTea), a 3D-aware flow-matching framework that imputes spot-level gene expression on an unprofiled section from its H&E and the measured expression of adjacent profiled sections. Our key idea is to take the measured expression at the same registered position on neighboring sections and feed this cross-section context to the flow model through a lightweight ControlNet, so that predictions follow anatomical continuity along z. To capture the discrete, zero-inflated nature of counts, the flow starts from a learned zero-inflated negative binomial (ZINB) prior that, on an unprofiled section, is predicted from the measured expression of the nearest profiled section. A global attention block with a small set of inducing tokens adds whole-slide context at a cost linear in the number of spots, so training and inference scale to large 3D ST datasets. Across three ST datasets spanning different tissue types and resolutions, HoloTea consistently improves 3D expression accuracy and generalization compared to 2D and 3D baselines. We envision HoloTea advancing the creation of accurate 3D virtual tissues, ultimately accelerating biomarker discovery and deepening our understanding of disease. Code is available at https://github.com/Lotfollahi-lab/HoloTea.