# MMSpa is a deep learning-based tool that enhances the identification of spatial domains in spatial transcriptomics studies

**Authors:** Yi Liu, Yixiao Zhai, Pinglu Zhang, Quan Zou, Ximei Luo

PMC · DOI: 10.1371/journal.pbio.3003580 · PLOS Biology · 2026-01-05

## TL;DR

MMSpa is a new deep learning tool that improves the identification of spatial domains in spatial transcriptomics by better capturing gene expression patterns and tissue boundaries.

## Contribution

MMSpa introduces a masked graph attention autoencoder with an edge-removal strategy to enhance spatial domain identification in transcriptomics.

## Key findings

- MMSpa outperforms existing methods in identifying spatial domains across multiple ST technologies and platforms.
- MMSpa excels in detecting finer-grained functional tissue domains in complex and heterogeneous tissues.
- The method reveals clearer domain boundaries and compensates for the lack of spatial annotation in histopathology.

## Abstract

Spatial transcriptome (ST) technologies have transformed the study of tissue structure by retaining the spatial distribution of gene expression. One major challenge in accurately identifying spatial domains is to extract domain-related information from spatial locations and gene expression. Here, we propose MMSpa, a masked graph attention autoencoder framework specifically designed to improve spatial domain identification. MMSpa incorporates an edge-removal strategy to construct an enhanced spatial graph to fundamentally address cross-domain interference and characterize clearer domain boundaries. By focusing on masked gene expression reconstruction, MMSpa learns stable latent representations that capture core biological features, facilitating the identification of similar spatial subdomains and detecting domain differences across biological samples at the same developmental stage. Comparative analyses using ST datasets from multiple ST technologies and platforms demonstrated that MMSpa outperforms existing methods across various accuracy assessments. Notably, MMSpa excels in challenging scenarios involving highly heterogeneous and complex tissues, and can reveal finer-grained functional tissue domains obscured by other methods. This superior capability positions MMSpa as a powerful tool for uncovering new biological insights and compensating for the lack of spatial annotation in histopathology.

Accurately extracting domain-related information from spatial locations and gene expression is a challenge in spatial transcriptomics analysis. This study develops a masked graph attention autoencoder framework called MMSpa that enhances spatial domain identification in spatial transcriptomics by reducing cross-domain interference and clarifying tissue boundaries.

## Full-text entities

- **Genes:** Kcne2 (potassium voltage-gated channel, Isk-related subfamily, gene 2) [NCBI Gene 246133] {aka 2200002I16Rik, MiRP1}, Akt1 (Akt serine/threonine kinase 1) [NCBI Gene 11651] {aka Akt, LTR-akt, PKB, PKB/Akt, PKBalpha, Rac}, Slc16a8 (solute carrier family 16 (monocarboxylic acid transporters), member 8) [NCBI Gene 57274] {aka Mct3}, Ttr (transthyretin) [NCBI Gene 22139] {aka prealbumin}, Alx3 (aristaless-like homeobox 3) [NCBI Gene 11694], Vim (vimentin) [NCBI Gene 22352], Dsg1a (desmoglein 1 alpha) [NCBI Gene 13510] {aka DG1, DGI, Dsg1, dsg1-alpha}, Car1 (carbonic anhydrase 1) [NCBI Gene 12346] {aka Ca1, Car-1}, Hip1 (huntingtin interacting protein 1) [NCBI Gene 215114] {aka 2610109B09Rik, A930014B11Rik, E130315I21Rik, mKIAA4113}, Pik3r1 (phosphoinositide-3-kinase regulatory subunit 1) [NCBI Gene 18708] {aka PI3K, p50alpha, p55alpha, p85alpha}, Lhx2 (LIM homeobox protein 2) [NCBI Gene 16870] {aka LH2A, Lh-2, Lim2, ap, apterous}, Cldn2 (claudin 2) [NCBI Gene 12738], Car2 (carbonic anhydrase 2) [NCBI Gene 12349] {aka CAII, Ca2, Car-2, Ltw-5, Lvtw-5}, Myog (myogenin) [NCBI Gene 17928] {aka MYF4, bHLHc3, myo}, Zic4 (zinc finger protein of the cerebellum 4) [NCBI Gene 22774], Aqp1 (aquaporin 1) [NCBI Gene 11826] {aka CHIP28}, Fgfr1 (fibroblast growth factor receptor 1) [NCBI Gene 14182] {aka Eask, FGFR-I, FLG, Fgfr-1, Flt-2, Fr1}, Cldn1 (claudin 1) [NCBI Gene 12737], Clic6 (chloride intracellular channel 6) [NCBI Gene 209195] {aka 5730466J16Rik, CLIC1L}, Zic1 (zinc finger protein of the cerebellum 1) [NCBI Gene 22771] {aka ZIC, ZNF201}, Foxj1 (forkhead box J1) [NCBI Gene 15223] {aka FKHL-13, HFH-4, Hfh4}, Csf2 (colony stimulating factor 2 (granulocyte-macrophage)) [NCBI Gene 12981] {aka CSF, Csfgm, GMCSF, Gm-CSf, MGI-IGM}, Tekt1 (tektin 1) [NCBI Gene 21689] {aka MT14}, Ube2k (ubiquitin-conjugating enzyme E2K) [NCBI Gene 53323] {aka D5Ertd601e, E2-25k, HIP-2, Hip2, Hypg, Lig}, Scube1 (signal peptide, CUB domain, EGF-like 1) [NCBI Gene 64706] {aka 7330410C13Rik, A630023E24Rik}, Spef2 (sperm flagellar 2) [NCBI Gene 320277] {aka C230086A09Rik}, Malat1 (metastasis associated lung adenocarcinoma transcript 1 (non-coding RNA)) [NCBI Gene 72289] {aka 2210401K01Rik, 9430072K23Rik, Neat2}
- **Diseases:** IDC (MESH:D044584), WM (MESH:D056784), ARI (MESH:D000275), breast cancer (MESH:D001943), NMI (MESH:C537354), UMAP (MESH:C567162), HIP (OMIM:142700), cognitive disorders (MESH:D003072), ST (MESH:D008569), neurodegenerative (MESH:D019636), PDAC (MESH:D021441), HIPs (MESH:D000092223), metastasis (MESH:D009362), tumorigenic (MESH:D002471), LCIS (MESH:D000071960), RHP (MESH:D001927), psychiatric conditions (MESH:D001523), GNNs (MESH:D015441), DCIS (MESH:D002285), Cancer (MESH:D009369)
- **Chemicals:** BP (MESH:C038809), eosin (MESH:D004801), MAEST (-), hematoxylin (MESH:D006416)
- **Species:** Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606]
- **Mutations:** S18E, S15D, S12G, S17A, S13C, S11D, S12D, S11A, S18F, S13D, S12F, S18A, S18D, S12C, S11C, S14C, S13A

## Full text

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## Figures

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## References

114 references — full list in the complete paper: https://tomesphere.com/paper/PMC12768284/full.md

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Source: https://tomesphere.com/paper/PMC12768284