MORPHE: Bridging Image Generation and Spatial Omics for Tissue Synthesis

Abstract

Spatially resolved omics technologies reveal tissue organization at single-cell resolution but remain limited by the cost of the assays, incomplete spatial coverage, 2D-only imaging, and experimental artifacts. These factors motivate the need for in silico methods that can reconstruct or extend tissue context beyond what current spatial measurements provide. We present MORPHE (MOdeling of stRuctured sPatial High-dimensional Embeddings), an AI framework that learns to synthesize biologically faithful tissue architecture directly from spatial-omics data. MORPHE introduces a graph-informed probabilistic embedding that maps discrete cell identities and their spatial relationships into a continuous RGB-like latent space compatible with diffusion modeling. This representational bridge enables spatial cellular maps to leverage large pre-trained image-generative models while preserving biological interpretability upon decoding. By modeling cells as the fundamental units of generation and learning how their identities and spatial relationships collectively give rise to large-scale tissue structure, MORPHE enables generation and reconstruction of tissue architecture at single-cell resolution. We applied the method across large-scale single-cell proteomic datasets from the intestine and single-cell transcriptomic datasets from the brain, showing computational scalability acrosss millions of cells. We used MORPHE on these datasets to outpaint beyond experimentally restricted fields of view, inpaint missing or experimentally damaged tissue regions, and perform cross-tissue imputation, connecting separated tissue regions into a single contiguous sample in both 2D and 3D. MORPHE represents a new class of tissue generation algorithms that will help solve current limitations and challenges with single-cell spatial-omics datasets.