{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T16:47:06Z","timestamp":1785775626306,"version":"3.56.0"},"reference-count":59,"publisher":"Wiley","issue":"43","license":[{"start":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T00:00:00Z","timestamp":1778371200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T00:00:00Z","timestamp":1778371200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2024YFF1206603"],"award-info":[{"award-number":["2024YFF1206603"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["62325204"],"award-info":[{"award-number":["62325204"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["62572130"],"award-info":[{"award-number":["62572130"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["62272326"],"award-info":[{"award-number":["62272326"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Recent advances in spatial multi\u2010omics technologies have enabled the simultaneous profiling of multiple molecular layers within the same tissue slice, providing unprecedented opportunities to investigate tissue spatial organization. However, most existing computational methods identify spatial domains in a purely data\u2010driven manner, rarely uncovering the interpretable multi\u2010omics regulatory mechanisms that underlie spatial heterogeneity. Here, we introduce SMOReg, a spatial multi\u2010omics hierarchical graph learning framework that embeds cross\u2010omics regulatory patterns into spot representations via cross\u2010graph matching, thereby yielding fine\u2010grained spatial domains with enhanced biological interpretability. Evaluated on paired spatial transcriptomic and proteomic datasets from diverse tissues, SMOReg consistently outperformed existing methods across multiple metrics. Notably, SMOReg uncovered fine\u2010grained spatial domains characterized by biologically interpretable multi\u2010layer regulatory signatures that competing approaches overlooked. It successfully distinguished the germinal center light zone and dark zone in human tonsil, which are histologically well\u2010established yet spatially ambiguous compartments, and revealed their specialized regulatory pathways driving B\u2010cell proliferation and affinity maturation. SMOReg thus provides a powerful framework for deciphering the interplay between spatial domain heterogeneity and underlying multi\u2010omics regulation, significantly advancing the interpretability of spatial domains in complex\u00a0tissues.<\/jats:p>","DOI":"10.1002\/advs.75574","type":"journal-article","created":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T18:02:23Z","timestamp":1778436143000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Decoding Spatial Heterogeneity and Multi\u2010Omics Regulation with Hierarchical Graph Learning"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7171-9547","authenticated-orcid":false,"given":"Jiazhou","family":"Chen","sequence":"first","affiliation":[{"name":"School of Computer Science and Technology Guangdong University of Technology Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahui","family":"Xie","sequence":"additional","affiliation":[{"name":"School of Computer Science and Technology South China University of Technology Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Liao","sequence":"additional","affiliation":[{"name":"School of Computer Science and Technology South China University of Technology Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyu","family":"Li","sequence":"additional","affiliation":[{"name":"School of Future Technology South China University of Technology Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longqi","family":"Liu","sequence":"additional","affiliation":[{"name":"BGI\u2010Shenzhen Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Gao","sequence":"additional","affiliation":[{"name":"Computer Science Program, Computer, Electrical and Mathematical Sciences and Engineering Division King Abdullah University of Science and Technology (KAUST) King Abdullah Kingdom of Saudi Arabia"},{"name":"Center of Excellence for Smart Health (KCSH) King Abdullah University of Science and Technology King Abdullah Kingdom of Saudi Arabia"},{"name":"Center of Excellence on Generative AI King Abdullah University of Science and Technology King Abdullah Kingdom of Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2747-7234","authenticated-orcid":false,"given":"Hongmin","family":"Cai","sequence":"additional","affiliation":[{"name":"School of Future Technology South China University of Technology Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,10]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03634-9"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-neuro-100520-082639"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-024-00841-1"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf2403"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-019-0129-z"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.10.026"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-28445-y"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-022-01536-3"},{"key":"e_1_2_7_10_1","doi-asserted-by":"crossref","unstructured":"S.Liao Y.Heng W.Liu et\u00a0al. \u201cIntegrated Spatial Transcriptomic and Proteomic Analysis of Fresh Frozen Tissue Based on Stereo\u2010Seq \u201dbioRxiv(2023): 2023\u201304.","DOI":"10.1101\/2023.04.28.538364"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-43458-x"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-023-01676-0"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.04.048"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-020-01050-x"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-023-01909-9"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-29439-6"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-44367-9"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-024-01283-x"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-024-02316-4"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-024-02257-y"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-024-02574-2"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-55204-y"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-023-00618-5"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-023-01715-w"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-29356-8"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btae433"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btae466"},{"key":"e_1_2_7_28_1","doi-asserted-by":"crossref","unstructured":"Z.Zhang J.Han L.Song andX.Zhang \u201cCESPGRN: Inferring Cell\u2010Specific Gene Regulatory Networks from Single\u2010Cell Multi\u2010Omics and Spatial Data \u201dbioRxiv(2022): 2022\u201303.","DOI":"10.1101\/2022.03.03.482887"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-10-387"},{"key":"e_1_2_7_30_1","unstructured":"R. L.SorensonandT. C.Brelje \u201cMHS 213 Lymph Nodes \u201dHistology Guide: Virtual Microscopy Laboratory University of Minnesota Chapter 10 \u2013 Lymphoid System(2025) https:\/\/histologyguide.com\/gallery\/10\u2010lymphoid\u2010system.html?page=6."},{"key":"e_1_2_7_31_1","unstructured":"R. L.SorensonandT. C.Brelje \u201cMH 081A Palatine Tonsil \u201dHistology Guide: Virtual Microscopy Laboratory University of Minnesota Chapter 10 \u2013 Lymphoid System(2025).https:\/\/histologyguide.com\/gallery\/10\u2010lymphoid\u2010system.html?page=7."},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3804"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1211427109"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac1000"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri2491"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M009063200"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20151620"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M701165200"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpbi.5"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aay3224"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2200572"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.12"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-023-01102-0"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.02.080"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.imlet.2024.106904"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1176009"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3667"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad1044"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.202308049"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-017-1382-0"},{"key":"e_1_2_7_51_1","doi-asserted-by":"crossref","unstructured":"G. O.Consortium \u201cThe Gene Ontology (GO) Database and Informatics Resource \u201dNucleic Acids Research32 no. suppl_1 (2004):D258\u2013D261.","DOI":"10.1093\/nar\/gkh036"},{"key":"e_1_2_7_52_1","doi-asserted-by":"crossref","unstructured":"G.Qian A.Abualshour G.Li A.Thabet andB.Ghanem \u201cPU\u2010GCN: Point Cloud Upsampling Using Graph Convolutional Networks \u201d inProceedings of the IEEE\/CVF Conference on Computer Vision and Pattern Recognition(2021):11683\u201311692.","DOI":"10.1109\/CVPR46437.2021.01151"},{"key":"e_1_2_7_53_1","volume-title":"Permutation Tests: A Practical Guide to Resampling Methods for Testing Hypotheses","author":"Good P.","year":"2013"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac194"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.211"},{"key":"e_1_2_7_56_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae979"},{"key":"e_1_2_7_57_1","unstructured":"\u201cUniProt: The Universal Protein Knowledgebase in 2025 \u201dNucleic Acids Research53 no.D1(2025):D609\u2013D617."},{"key":"e_1_2_7_58_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw1092"},{"key":"e_1_2_7_59_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad1025"},{"key":"e_1_2_7_60_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad960"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.75574","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/advs.75574","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.75574","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T16:02:12Z","timestamp":1785772932000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.75574"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,10]]},"references-count":59,"journal-issue":{"issue":"43","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1002\/advs.75574"],"URL":"https:\/\/doi.org\/10.1002\/advs.75574","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,10]]},"assertion":[{"value":"2026-03-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-28","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e75574"}}