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

arXiv: https://arxiv.org/abs/2511.14613 · HTML: https://mlsanity.com/paper/2511.14613/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Placed in Medical imaging and segmentation, one of 14 directions in Diffusion models.
- Builds on 13 of its 43 references that are in the map.
- First posted on arXiv 18 Nov 2025.

## Placed in

- Diffusion models / [Medical imaging and segmentation](https://mlsanity.com/diffusion/medical-imaging-and-segmentation/)

## Builds on (most cited first, 13 of 13)

- [Graph Attention Networks](https://mlsanity.com/paper/1710.10903/) (2017)
- [Flow Matching for Generative Modeling](https://mlsanity.com/paper/2210.02747/) (2022)
- [Adding Conditional Control to Text-to-Image Diffusion Models](https://mlsanity.com/paper/2302.05543/) (2023)
- [Scaling Rectified Flow Transformers for High-Resolution Image Synthesis](https://mlsanity.com/paper/2403.03206/) (2024)
- [Flow Straight and Fast: Learning to Generate and Transfer Data with Rectified Flow](https://mlsanity.com/paper/2209.03003/) (2022)
- [Self supervised contrastive learning for digital histopathology](https://mlsanity.com/paper/2011.13971/) (2020)
- [HEST-1k: A Dataset for Spatial Transcriptomics and Histology Image Analysis](https://mlsanity.com/paper/2406.16192/) (2024)
- [Accurate Spatial Gene Expression Prediction by integrating Multi-resolution features](https://mlsanity.com/paper/2403.07592/) (2024)
- [Diffusion Generative Modeling for Spatially Resolved Gene Expression Inference from Histology Images](https://mlsanity.com/paper/2501.15598/) (2025)
- [Multimodal contrastive learning for spatial gene expression prediction using histology images](https://mlsanity.com/paper/2407.08216/) (2024)
- [Scalable Generation of Spatial Transcriptomics from Histology Images via Whole-Slide Flow Matching](https://mlsanity.com/paper/2506.05361/) (2025)
- [ASIGN: An Anatomy-aware Spatial Imputation Graphic Network for 3D Spatial Transcriptomics](https://mlsanity.com/paper/2412.03026/) (2024)
- [SpaRED benchmark: Enhancing Gene Expression Prediction from Histology Images with Spatial Transcriptomics Completion](https://mlsanity.com/paper/2407.13027/) (2024)

## Abstract (arXiv)

A scalable and robust 3D tissue transcriptomics profile can enable a holistic understanding of tissue organization and provide deeper insights into human biology and disease. Most predictive algorithms that infer ST directly 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 from H&E while explicitly using information from adjacent sections. Our key idea is to retrieve morphologically corresponding spots on neighboring slides in a shared feature space and fuse this cross section context into a lightweight ControlNet, allowing conditioning to follow anatomical continuity. To better capture the count nature of the data, we introduce a 3D-consistent prior for flow matching that combines a learned zero-inflated negative binomial (ZINB) prior with a spatial-empirical prior constructed from neighboring sections. A global attention block introduces 3D H&E scaling linearly with the number of spots in the slide, enabling training and inference on large 3D ST datasets. Across three spatial transcriptomics 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.