{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:14:36Z","timestamp":1785413676604,"version":"3.56.0"},"posted":{"date-parts":[[2026,2,22]]},"group-title":"Genomics","reference-count":60,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,22]],"date-time":"2026-02-22T00:00:00Z","timestamp":1771718400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R01HG013185"],"award-info":[{"award-number":["R01HG013185"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01LM014592"],"award-info":[{"award-number":["R01LM014592"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U19NS135582"],"award-info":[{"award-number":["U19NS135582"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01HL171595"],"award-info":[{"award-number":["R01HL171595"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U01CA294518"],"award-info":[{"award-number":["U01CA294518"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Understanding spatial organization of cells is critical for deciphering tissue function and disease. Single-cell RNA-sequencing (scRNA-seq) profiles transcriptomes at scale but loses spatial context, while spatial transcriptomics (ST) preserves spatial information but is constrained by cost and gene coverage. Here, we present REMAP, a deep learning framework that integrates gene expression with neighborhood-level gene-gene covariance to reconstruct multi-scale spatial organization of scRNA-seq data using one or multiple ST references. Across 2D and 3D mouse brain, human fetal cortex, and seven human cancer types, REMAP consistently outperformed existing approaches. Applied to a human multiple sclerosis atlas, REMAP resolved microglial neighborhood heterogeneity, and identified a rare pro-inflammatory microglia-astrocyte subpopulation. Across diverse cancers, REMAP recovered conserved spatially-defined cancer-associated fibroblast subtypes with known prognostic significance. By transforming cost-efficient single-cell datasets into spatially interpretable tissue maps, REMAP enables spatial hypothesis generation, microenvironment discovery, and population-scale inference of conserved and perturbed architectural principles in human disease.<\/jats:p>","DOI":"10.64898\/2026.02.21.707167","type":"posted-content","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T02:55:11Z","timestamp":1771815311000},"source":"Crossref","is-referenced-by-count":0,"title":["Reconstructing multi-scale tissue spatial architecture from single-cell RNA-seq with REMAP"],"prefix":"10.64898","author":[{"given":"Shunzhou","family":"Jiang","sequence":"first","affiliation":[{"name":"Statistical Center for Single-Cell and Spatial Genomics, Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle","family":"Coleman","sequence":"additional","affiliation":[{"name":"Department of Computational Biomedicine, Cedars Sinai Medical Center, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihao","family":"Chen","sequence":"additional","affiliation":[{"name":"Statistical Center for Single-Cell and Spatial Genomics, Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaitian","family":"Jin","sequence":"additional","affiliation":[{"name":"Statistical Center for Single-Cell and Spatial Genomics, Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunhe","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong Heon","family":"Lee","sequence":"additional","affiliation":[{"name":"Statistical Center for Single-Cell and Spatial Genomics, Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae Hyun","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Xiao","sequence":"additional","affiliation":[{"name":"Statistical Center for Single-Cell and Spatial Genomics, Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Jin","sequence":"additional","affiliation":[{"name":"Statistical Center for Single-Cell and Spatial Genomics, Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8357-8585","authenticated-orcid":false,"given":"Christopher A.","family":"Walsh","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Department of Pediatrics, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA, USA"},{"name":"Howard Hughes Medical Institute, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuyu","family":"Qian","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA"},{"name":"Center for Brain Research in Development, Genetics, and Engineering (BRIDGE), Children\u2019s Hospital of Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linghua","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyao","family":"Li","sequence":"additional","affiliation":[{"name":"Statistical Center for Single-Cell and Spatial Genomics, Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026022417200729000_2026.02.21.707167v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3832"},{"key":"2026022417200729000_2026.02.21.707167v1.2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa6090"},{"key":"2026022417200729000_2026.02.21.707167v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-019-0129-z"},{"key":"2026022417200729000_2026.02.21.707167v1.4","doi-asserted-by":"publisher","DOI":"10.1002\/bies.201900221"},{"key":"2026022417200729000_2026.02.21.707167v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03634-9"},{"key":"2026022417200729000_2026.02.21.707167v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-022-01409-2"},{"key":"2026022417200729000_2026.02.21.707167v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.csbj.2021.06.052"},{"key":"2026022417200729000_2026.02.21.707167v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-021-00370-8"},{"key":"2026022417200729000_2026.02.21.707167v1.9","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-022-02653-7"},{"key":"2026022417200729000_2026.02.21.707167v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-024-02363-x"},{"key":"2026022417200729000_2026.02.21.707167v1.11","doi-asserted-by":"publisher","DOI":"10.1002\/smtd.202401194"},{"key":"2026022417200729000_2026.02.21.707167v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-021-01264-7"},{"key":"2026022417200729000_2026.02.21.707167v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15968-5"},{"key":"2026022417200729000_2026.02.21.707167v1.14","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1773-3"},{"key":"2026022417200729000_2026.02.21.707167v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.patter.2024.101022"},{"key":"2026022417200729000_2026.02.21.707167v1.16","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-39895-3"},{"key":"2026022417200729000_2026.02.21.707167v1.17","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1012991"},{"key":"2026022417200729000_2026.02.21.707167v1.18","doi-asserted-by":"publisher","DOI":"10.1101\/2025.02.13.638045"},{"key":"2026022417200729000_2026.02.21.707167v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-022-00951-w"},{"key":"2026022417200729000_2026.02.21.707167v1.20","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-01664-3"},{"key":"2026022417200729000_2026.02.21.707167v1.21","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-024-02193-4"},{"key":"2026022417200729000_2026.02.21.707167v1.22","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-023-01588-4"},{"key":"2026022417200729000_2026.02.21.707167v1.23","doi-asserted-by":"publisher","DOI":"10.1101\/2025.02.25.640190"},{"key":"2026022417200729000_2026.02.21.707167v1.24","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-08338-4"},{"key":"2026022417200729000_2026.02.21.707167v1.25","doi-asserted-by":"publisher","DOI":"10.1101\/gr.271874.120"},{"key":"2026022417200729000_2026.02.21.707167v1.26","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-39608-w"},{"key":"2026022417200729000_2026.02.21.707167v1.27","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03500-8"},{"key":"2026022417200729000_2026.02.21.707167v1.28","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03705-x"},{"key":"2026022417200729000_2026.02.21.707167v1.29","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-09010-1"},{"key":"2026022417200729000_2026.02.21.707167v1.30","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-025-02193-3"},{"key":"2026022417200729000_2026.02.21.707167v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-43458-x"},{"key":"2026022417200729000_2026.02.21.707167v1.32","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06808-9"},{"key":"2026022417200729000_2026.02.21.707167v1.33","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-024-01796-z"},{"key":"2026022417200729000_2026.02.21.707167v1.34","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-023-02019-9"},{"key":"2026022417200729000_2026.02.21.707167v1.35","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0619-0"},{"key":"2026022417200729000_2026.02.21.707167v1.36","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-021-01139-4"},{"key":"2026022417200729000_2026.02.21.707167v1.37","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-023-00709-6"},{"key":"2026022417200729000_2026.02.21.707167v1.38","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms2230"},{"key":"2026022417200729000_2026.02.21.707167v1.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2024.11.016"},{"key":"2026022417200729000_2026.02.21.707167v1.40","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-49312-y"},{"key":"2026022417200729000_2026.02.21.707167v1.41","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-89786-0"},{"key":"2026022417200729000_2026.02.21.707167v1.42","doi-asserted-by":"publisher","DOI":"10.1038\/nature21029"},{"key":"2026022417200729000_2026.02.21.707167v1.43","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-0969-x"},{"key":"2026022417200729000_2026.02.21.707167v1.44","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2023.02.015"},{"key":"2026022417200729000_2026.02.21.707167v1.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2025.03.004"},{"key":"2026022417200729000_2026.02.21.707167v1.46","doi-asserted-by":"publisher","DOI":"10.1186\/s12935-021-01896-x"},{"key":"2026022417200729000_2026.02.21.707167v1.47","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-10-1824"},{"key":"2026022417200729000_2026.02.21.707167v1.48","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.956270"},{"key":"2026022417200729000_2026.02.21.707167v1.49","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-21-1714"},{"key":"2026022417200729000_2026.02.21.707167v1.50","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-23-1183"},{"key":"2026022417200729000_2026.02.21.707167v1.51","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1911951117"},{"key":"2026022417200729000_2026.02.21.707167v1.52","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-021-01908-8"},{"key":"2026022417200729000_2026.02.21.707167v1.53","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygeno.2020.11.012"},{"key":"2026022417200729000_2026.02.21.707167v1.54","first-page":"268","article-title":"Stress sensor Gadd45 genes as therapeutic targets in cancer","volume":"7","year":"2009","journal-title":"Cancer Ther"},{"key":"2026022417200729000_2026.02.21.707167v1.55","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2025.09.001"},{"key":"2026022417200729000_2026.02.21.707167v1.56","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-54306-x"},{"key":"2026022417200729000_2026.02.21.707167v1.57","doi-asserted-by":"publisher","DOI":"10.1101\/2025.06.16.658716"},{"key":"2026022417200729000_2026.02.21.707167v1.58","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21246-9"},{"key":"2026022417200729000_2026.02.21.707167v1.59","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-017-1382-0"},{"key":"2026022417200729000_2026.02.21.707167v1.60","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-024-01020-z"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.02.21.707167","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T01:20:12Z","timestamp":1771982412000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.02.21.707167"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,22]]},"references-count":60,"URL":"https:\/\/doi.org\/10.64898\/2026.02.21.707167","relation":{},"subject":[],"published":{"date-parts":[[2026,2,22]]},"subtype":"preprint"}}