{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T14:09:40Z","timestamp":1761746980916,"version":"build-2065373602"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T00:00:00Z","timestamp":1761696000000},"content-version":"vor","delay-in-days":59,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["T2341022","42450084","12322119","T2341022","12501670","12371485","42450084"],"award-info":[{"award-number":["T2341022","42450084","12322119","T2341022","12501670","12371485","42450084"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Key Research and Developmen Program of China","award":["2023YFF1204700"],"award-info":[{"award-number":["2023YFF1204700"]}]},{"DOI":"10.13039\/501100021171","name":"Guangdong Basic and Applied Basic Research Foundation","doi-asserted-by":"publisher","award":["2024A1515011797","2022A1515110759","2023A1515110176","2025A1515011988"],"award-info":[{"award-number":["2024A1515011797","2022A1515110759","2023A1515110176","2025A1515011988"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Guangdong Provincial Key Laboratory of Mathematical and Neural Dynamical Systems","award":["2024B1212010004"],"award-info":[{"award-number":["2024B1212010004"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,8,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Multicellular organisms are composed of diverse cell types that must coordinate their behaviors through communication. Cell\u2013cell communication (CCC) is essential for growth, development, differentiation, and immune response. Recent computational methods have leveraged single-cell RNA sequencing (scRNA-seq) to infer CCC via ligand\u2013receptor interactions (LRIs), with most approaches focusing on pairwise interactions. However, many biological processes are driven by the coordinated action of multiple cell types, underscoring the need to model higher-order cellular interactions beyond pairwise interactions. Inspired by principles of network diffusion and epidemic dynamics, we first model the receptor expression as: a Poisson-distributed random variable biologically regulated by the collective signaling of multiple ligand-producing cell types. Then, we propose Hi-C3, a unified statistical inference-based framework for inferring both conventional pairwise and new higher-order CCC patterns from scRNA-seq data, which is solved via an efficient likelihood-based (EM) algorithm. Particularly, Hi-C3 employed a modified PageRank algorithm to assess the importance of individual cells or cell types within the higher-order network, revealing key cellular communication hubs supported by independent spatial and biological evidence. When applied to diverse datasets from Arabidopsis thaliana and colorectal cancer, Hi-C3 achieved comparable performance to state-of-the-art methods in the inferring pairwise communication while uniquely uncovering complex higher-order cellular communication structures. Collectively, Hi-C3 offers a powerful statistical model and computational framework for uncovering complex and coordinated multicellular signaling structures disregarded by pairwise communication inference methods, and offers novel biology network insights into the logic of cellular organization and communication in both development and disease.<\/jats:p>","DOI":"10.1093\/bib\/bbaf568","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T11:28:00Z","timestamp":1759750080000},"source":"Crossref","is-referenced-by-count":0,"title":["Hi-C3: a statistical inference-based model for reconstructing higher-order cell\u2013cell communication networks"],"prefix":"10.1093","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1489-0609","authenticated-orcid":false,"given":"Yuyan","family":"Tong","sequence":"first","affiliation":[{"name":"School of Mathematics , South China University of Technology, No. 381 Wushan Road, Tianhe District, Guangzhou 510640, Guangdong,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0565-927X","authenticated-orcid":false,"given":"Renhao","family":"Hong","sequence":"additional","affiliation":[{"name":"School of Mathematics , South China University of Technology, No. 381 Wushan Road, Tianhe District, Guangzhou 510640, Guangdong,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meng","family":"Li","sequence":"additional","affiliation":[{"name":"School of Mathematics , Foshan University, No. 18 Jiangwan 1st Road, Chancheng District, Foshan 528000, Guangdong,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Na","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Mathematics , South China University of Technology, No. 381 Wushan Road, Tianhe District, Guangzhou 510640, Guangdong,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weihao","family":"Deng","sequence":"additional","affiliation":[{"name":"School of Mathematics , Foshan University, No. 18 Jiangwan 1st Road, Chancheng District, Foshan 528000, Guangdong,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Tang","sequence":"additional","affiliation":[{"name":"School of Mathematics , Foshan University, No. 18 Jiangwan 1st Road, Chancheng District, Foshan 528000, Guangdong,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tao","family":"Zeng","sequence":"additional","affiliation":[{"name":"Guangzhou National Laboratory , Xingji 4th Road, Haizhu District, Guangzhou 510005, Guangdong,","place":["China"]},{"name":"GMU-GIBH Joint School of Life Sciences , The Guangdong\u2013Hong Kong\u2013Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Laboratory, Guangzhou Medical University, Xinzao Town, Panyu District, Guangzhou 511495, Guangdong,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4547-8695","authenticated-orcid":false,"given":"Rui","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Mathematics , South China University of Technology, No. 381 Wushan Road, Tianhe District, Guangzhou 510640, Guangdong,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,10,29]]},"reference":[{"key":"2025102907483092000_ref1","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1038\/s41576-020-00292-x","article-title":"Deciphering cell\u2013cell interactions and communication from gene expression","volume":"22","author":"Armingol","year":"2021","journal-title":"Nat Rev Genet"},{"key":"2025102907483092000_ref2","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.coisb.2021.03.007","article-title":"The landscape of cell\u2013cell communication through single-cell transcriptomics","volume":"26","author":"Almet","year":"2021","journal-title":"Curr Opin Syst Biol"},{"key":"2025102907483092000_ref3","doi-asserted-by":"publisher","first-page":"3224","DOI":"10.1038\/s41467-022-30755-0","article-title":"Comparison of methods and resources for cell-cell communication inference from single-cell RNA-Seq data","volume":"13","author":"Dimitrov","year":"2022","journal-title":"Nat Commun"},{"key":"2025102907483092000_ref4","doi-asserted-by":"publisher","first-page":"E679","DOI":"10.1073\/pnas.1516503113","article-title":"Cell\u2013cell communication enhances the capacity of cell ensembles to sense shallow gradients during morphogenesis","volume":"113","author":"Ellison","year":"2016","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025102907483092000_ref5","doi-asserted-by":"publisher","first-page":"1080","DOI":"10.1093\/bib\/bbz040","article-title":"Single-cell transcriptome-based multilayer network biomarker for predicting prognosis and therapeutic response of gliomas","volume":"21","author":"Zhang","year":"2020","journal-title":"Brief Bioinform"},{"key":"2025102907483092000_ref6","doi-asserted-by":"publisher","first-page":"eadv3316","DOI":"10.1126\/sciadv.adv3316","article-title":"Multiscale mathematical model-informed reinforcement learning optimizes combination treatment scheduling in glioblastoma evolution","volume":"11","author":"Liu","year":"2025","journal-title":"Sci Adv"},{"key":"2025102907483092000_ref7","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1186\/s13578-021-00635-z","article-title":"Applications and analytical tools of cell communication based on ligand-receptor interactions at single cell level","volume":"11","author":"Ma","year":"2021","journal-title":"Cell Biosci"},{"key":"2025102907483092000_ref8","doi-asserted-by":"publisher","first-page":"7866","DOI":"10.1038\/ncomms8866","article-title":"A draft network of ligand\u2013receptor-mediated multicellular signalling in human","volume":"6","author":"Ramilowski","year":"2015","journal-title":"Nat Commun"},{"key":"2025102907483092000_ref9","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1038\/s41596-024-01045-4","article-title":"CellChat for systematic analysis of cell\u2013cell communication from single-cell transcriptomics","volume":"20","author":"Jin","year":"2025","journal-title":"Nat Protoc"},{"key":"2025102907483092000_ref10","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1007\/s10565-019-09470-y","article-title":"Cell\u2013cell communication: old mystery and new opportunity","volume":"35","author":"Song","year":"2019","journal-title":"Cell Biol Toxicol"},{"key":"2025102907483092000_ref11","doi-asserted-by":"publisher","first-page":"866","DOI":"10.1007\/s13238-020-00727-5","article-title":"New avenues for systematically inferring cell-cell communication: through single-cell transcriptomics data","volume":"11","author":"Shao","year":"2020","journal-title":"Protein Cell"},{"key":"2025102907483092000_ref12","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1038\/nature14966","article-title":"Single-cell messenger RNA sequencing reveals rare intestinal cell types","volume":"525","author":"Gr\u00fcn","year":"2015","journal-title":"Nature"},{"key":"2025102907483092000_ref13","doi-asserted-by":"publisher","first-page":"e70068","DOI":"10.1002\/imt2.70068","article-title":"Quantifying cellular malignancy by tumor micro-environment measurement with multimodal fusion","author":"Zhu","year":"2025","journal-title":"iMeta"},{"key":"2025102907483092000_ref14","doi-asserted-by":"publisher","first-page":"111131","DOI":"10.1016\/j.isci.2024.111131","article-title":"Exploring structured molecular landscape from single-cell multi-omics data by an explainable multimodal model","volume":"27","author":"Tang","year":"2024","journal-title":"iScience"},{"key":"2025102907483092000_ref15","doi-asserted-by":"publisher","first-page":"629","DOI":"10.3389\/fgene.2019.00629","article-title":"Single-cell RNA sequencing-based computational analysis to describe disease heterogeneity","volume":"10","author":"Zeng","year":"2019","journal-title":"Front Genet"},{"key":"2025102907483092000_ref16","doi-asserted-by":"publisher","first-page":"1088","DOI":"10.1038\/s41467-021-21246-9","article-title":"Inference and analysis of cell-cell communication using CellChat","volume":"12","author":"Jin","year":"2021","journal-title":"Nat Commun"},{"key":"2025102907483092000_ref17","doi-asserted-by":"publisher","first-page":"2123","DOI":"10.1111\/pbi.13893","article-title":"PlantPhoneDB: a manually curated pan-plant database of ligand-receptor pairs infers cell\u2013cell communication","volume":"20","author":"Xu","year":"2022","journal-title":"Plant Biotechnol J"},{"key":"2025102907483092000_ref18","doi-asserted-by":"publisher","first-page":"eabf1356","DOI":"10.1126\/sciadv.abf1356","article-title":"CytoTalk: De novo construction of signal transduction networks using single-cell transcriptomic data","volume":"7","author":"Hu","year":"2021","journal-title":"Sci Adv"},{"key":"2025102907483092000_ref19","doi-asserted-by":"publisher","first-page":"5011","DOI":"10.1038\/s41467-020-18873-z","article-title":"Predicting cell-to-cell communication networks using NATMI","volume":"11","author":"Hou","year":"2020","journal-title":"Nat Commun"},{"key":"2025102907483092000_ref20","doi-asserted-by":"publisher","first-page":"e55","DOI":"10.1093\/nar\/gkaa183","article-title":"SingleCellSignalR: inference of intercellular networks from single-cell transcriptomics","volume":"48","author":"Cabello-Aguilar","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"2025102907483092000_ref21","doi-asserted-by":"publisher","first-page":"dev164038","DOI":"10.1242\/dev.164038","article-title":"Single-cell analysis of progenitor cell dynamics and lineage specification in the human fetal kidney","volume":"145","author":"Menon","year":"2018","journal-title":"Development"},{"key":"2025102907483092000_ref22","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1186\/s12859-023-05490-y","article-title":"Sctensor detects many-to-many cell\u2013cell interactions from single cell RNA-sequencing data","volume":"24","author":"Tsuyuzaki","year":"2023","journal-title":"BMC Bioinforma"},{"key":"2025102907483092000_ref23","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1038\/icb.1997.35","article-title":"The role of dendritic cells in T cell activation","volume":"75","author":"Ni","year":"1997","journal-title":"Immunol Cell Biol"},{"key":"2025102907483092000_ref24","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1038\/nri3902","article-title":"Immunological hallmarks of stromal cells in the tumour microenvironment","volume":"15","author":"Turley","year":"2015","journal-title":"Nat Rev Immunol"},{"key":"2025102907483092000_ref25","doi-asserted-by":"publisher","first-page":"3665","DOI":"10.1038\/s41467-022-31369-2","article-title":"Context-aware deconvolution of cell\u2013cell communication with tensor-cell2cell","volume":"13","author":"Armingol","year":"2022","journal-title":"Nat Commun"},{"key":"2025102907483092000_ref26","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbae436","article-title":"scHyper: reconstructing cell\u2013cell communication through hypergraph neural networks","volume":"25","author":"Li","year":"2024","journal-title":"Brief Bioinform"},{"key":"2025102907483092000_ref27","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1038\/nrg.2017.38","article-title":"Network propagation: a universal amplifier of genetic associations","volume":"18","author":"Cowen","year":"2017","journal-title":"Nat Rev Genet"},{"key":"2025102907483092000_ref28","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1103\/RevModPhys.87.925","article-title":"Epidemic processes in complex networks","volume":"87","author":"Pastor-Satorras","year":"2015","journal-title":"Rev Mod Phys"},{"key":"2025102907483092000_ref29","doi-asserted-by":"publisher","first-page":"3043","DOI":"10.1038\/s41467-022-30706-9","article-title":"Full reconstruction of simplicial complexes from binary contagion and Ising data","volume":"13","author":"Wang","year":"2022","journal-title":"Nat Commun"},{"key":"2025102907483092000_ref30","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1109\/79.543975","article-title":"The expectation-maximization algorithm","volume":"13","author":"Moon","year":"1996","journal-title":"IEEE Signal Process Mag"},{"key":"2025102907483092000_ref31","doi-asserted-by":"publisher","DOI":"10.1016\/j.ipm.2024.103948","article-title":"Higher-order structure based node importance evaluation in directed networks","volume":"62","author":"Li","year":"2025","journal-title":"Inf Process Manag"},{"key":"2025102907483092000_ref32","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1186\/s13059-019-1861-6","article-title":"Feature selection and dimension reduction for single-cell RNA-Seq based on a multinomial model","volume":"20","author":"Townes","year":"2019","journal-title":"Genome Biol"},{"key":"2025102907483092000_ref33","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1038\/s41586-021-04249-w","article-title":"RNA profiles reveal signatures of future health and disease in pregnancy","volume":"601","author":"Rasmussen","year":"2022","journal-title":"Nature"},{"key":"2025102907483092000_ref34","doi-asserted-by":"publisher","DOI":"10.1016\/j.ipm.2010.05.002"},{"key":"2025102907483092000_ref35","doi-asserted-by":"publisher","first-page":"5162","DOI":"10.21105\/joss.05162","article-title":"XGI: a Python package for higher-order interaction networks","volume":"8","author":"Landry","year":"2023","journal-title":"J Open Source Softw"},{"key":"2025102907483092000_ref36","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1038\/s41588-020-0636-z","article-title":"Lineage-dependent gene expression programs influence the immune landscape of colorectal cancer","volume":"52","author":"Lee","year":"2020","journal-title":"Nat Genet"},{"key":"2025102907483092000_ref37","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1016\/j.cell.2020.03.048","article-title":"Single-cell analyses inform mechanisms of myeloid-targeted therapies in colon cancer","volume":"181","author":"Zhang","year":"2020","journal-title":"Cell"},{"key":"2025102907483092000_ref38","doi-asserted-by":"publisher","first-page":"1268","DOI":"10.1016\/j.ccell.2024.06.009","article-title":"Spatiotemporal single-cell analysis decodes cellular dynamics underlying different responses to immunotherapy in colorectal cancer","volume":"42","author":"Chen","year":"2024","journal-title":"Cancer Cell"},{"key":"2025102907483092000_ref39","doi-asserted-by":"publisher","first-page":"840","DOI":"10.1016\/j.devcel.2019.02.022","article-title":"Spatiotemporal developmental trajectories in the Arabidopsis root revealed using high-throughput single-cell RNA sequencing","volume":"48","author":"Denyer","year":"2019","journal-title":"Dev Cell"},{"key":"2025102907483092000_ref40","doi-asserted-by":"publisher","first-page":"2197","DOI":"10.1093\/plcell\/koab101","article-title":"A single-cell view of the transcriptome during lateral root initiation in Arabidopsis thaliana","volume":"33","author":"Gala","year":"2021","journal-title":"Plant Cell"},{"key":"2025102907483092000_ref41","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1093\/plcell\/koaa060","article-title":"Distinct identities of leaf phloem cells revealed by single cell transcriptomics","volume":"33","author":"Kim","year":"2021","journal-title":"Plant Cell"},{"key":"2025102907483092000_ref42","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.1016\/j.devcel.2022.04.011","article-title":"The single-cell stereo-seq reveals region-specific cell subtypes and transcriptome profiling in Arabidopsis leaves","volume":"57","author":"Xia","year":"2022","journal-title":"Dev Cell"},{"key":"2025102907483092000_ref43","doi-asserted-by":"publisher","first-page":"D1053","DOI":"10.1093\/nar\/gkad933","article-title":"STOmicsDB: a comprehensive database for spatial transcriptomics data sharing, analysis and visualization","volume":"52","author":"Xu","year":"2024","journal-title":"Nucleic Acids Res"},{"key":"2025102907483092000_ref44","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1111\/jgh.12157","article-title":"Relationship between epithelial and stromal TRIM28 expression predicts survival in colorectal cancer patients","volume":"28","author":"Fitzgerald","year":"2013","journal-title":"J Gastroenterol Hepatol"},{"key":"2025102907483092000_ref45","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1038\/sj.onc.1210647","article-title":"Signal pathway profiling of epithelial and stromal compartments of colonic carcinoma reveals epithelial-mesenchymal transition","volume":"27","author":"Sheehan","year":"2008","journal-title":"Oncogene"},{"key":"2025102907483092000_ref46","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1158\/1541-7786.MCR-16-0156","volume-title":"Mol Cancer Res","author":"Mo","year":"2016"},{"key":"2025102907483092000_ref47","doi-asserted-by":"publisher","first-page":"1350","DOI":"10.1038\/nm.3967","article-title":"The consensus molecular subtypes of colorectal cancer","volume":"21","author":"Guinney","year":"2015","journal-title":"Nat Med"},{"key":"2025102907483092000_ref48","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1038\/nrc.2016.126","article-title":"Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer","volume":"17","author":"Dienstmann","year":"2017","journal-title":"Nat Rev Cancer"},{"key":"2025102907483092000_ref49","doi-asserted-by":"publisher","first-page":"2084","DOI":"10.3389\/fimmu.2018.02084","article-title":"ICAM-1-LFA-1 dependent CD8+ T-lymphocyte aggregation in tumor tissue prevents recirculation to draining lymph nodes","volume":"9","author":"Yanguas","year":"2018","journal-title":"Front Immunol"},{"key":"2025102907483092000_ref50","doi-asserted-by":"publisher","first-page":"0522","DOI":"10.34133\/research.0522","article-title":"eMCI: an explainable multimodal correlation integration model for unveiling spatial transcriptomics and intercellular Signaling","volume":"7","author":"Hong","year":"2024","journal-title":"Research"},{"key":"2025102907483092000_ref51","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbab584","article-title":"Vec2image: an explainable artificial intelligence model for the feature representation and classification of high-dimensional biological data by vector-to-image conversion","volume":"23","author":"Tang","year":"2022","journal-title":"Brief Bioinform"},{"key":"2025102907483092000_ref52","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1038\/ng755","article-title":"Bioinformatic identification of potential autocrine signaling loops in cancers from gene expression profiles","volume":"29","author":"Graeber","year":"2001","journal-title":"Nat Genet"}],"container-title":["Briefings in Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bib\/article-pdf\/26\/5\/bbaf568\/65023593\/bbaf568.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bib\/article-pdf\/26\/5\/bbaf568\/65023593\/bbaf568.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T11:48:38Z","timestamp":1761738518000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bib\/article\/doi\/10.1093\/bib\/bbaf568\/8305679"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,31]]},"references-count":52,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2025,8,31]]}},"URL":"https:\/\/doi.org\/10.1093\/bib\/bbaf568","relation":{},"ISSN":["1467-5463","1477-4054"],"issn-type":[{"value":"1467-5463","type":"print"},{"value":"1477-4054","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,9]]},"published":{"date-parts":[[2025,8,31]]},"article-number":"bbaf568"}}