Spatial transcriptomics offers unique opportunities to define the spatial organization of tissues and organs, such as the mouse brain. We address a key bottleneck in the analysis of organ-scale spatial transcriptomic data by establishing a workflow for self-supervised spatial domain detection that is scalable to multimillion-cell datasets. This workflow uses a self-supervised framework for learning latent representations of tissue spatial domains or niches. We use an encoder-decoder architecture, which we named CellTransformer, to hierarchically learn higher-order tissue features from lower-level cellular and molecular statistical patterns. Coupling our representation learning workflow with minibatched GPU-accelerated clustering algorithms allows us to scale to multi-million cell MERFISH datasets where other methods cannot. CellTransformer is effective at integrating cells across tissue sections, identifying domains highly similar to ones in existing ontologies such as Allen Mouse Brain Common Coordinate Framework (CCF) while allowing discovery of hundreds of uncataloged areas with minimal loss of domain spatial coherence. CellTransformer domains recapitulate previous neuroanatomical studies of areas in the subiculum and superior colliculus and characterize putatively uncataloged subregions in subcortical areas, which currently lack subregion annotation. CellTransformer is also capable of domain discovery in whole-brain Slide-seqV2 datasets. Our workflows enable complex multi-animal analyses, achieving nearly perfect consistency of up to 100 spatial domains in a dataset of four individual mice with nine million cells across more than 200 tissue sections. CellTransformer advances the state of the art for spatial transcriptomics by providing a performant solution for the detection of fine-grained tissue domains from spatial transcriptomics data. Defining the spatial organization of tissues and organs like the brain from large datasets is a major challenge. Here, authors introduce CellTransformer, an AI tool that defines spatial domains in the mouse brain based on spatial transcriptomics, a technology that measures which genes are active in different parts of tissue.
Researchers used an AI based on GPT architecture to map the brain, and they found it’s way more complex than we thought. Instead of the ~52 broad regions we’ve been working with, the AI identified about 1,300 distinct areas.
They trained a model called Cell Transformer on mouse brain scans. Instead of learning language, it learned the “grammar” of how brain cells are organized relative to their neighbors. It then automatically drew the borders between brain regions with high precision, revealing hidden neighborhoods we never knew existed.
With a map this detailed, researchers can now pinpoint the tiny, specific cellular areas involved in conditions like Alzheimer’s and depression. Having such a detailed map could massively speed up research and lead to much more targeted and effective treatments in the future.
