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Direct imaging of intact specimens by lightsheet and multiphoton microscopy, and computational reconstruction from serial sections, have established that 3D spatial context reveals cell and tissue organization inaccessible at single planes. Computational reconstruction in particular can leverage archived human tissue, benefiting from the cost-effectiveness, robustness, scalable storage, workflow compatibility, and century-long pathobiology knowledge of histology, and can integrate multiple spatial modalities. However, sectioning can introduce tears and folds, and computational alignment can further distort tissue integrity. Here we introduce SpaReg, a sparsity-based 3D reconstruction method spanning histology, spatial proteomics and spatial transcriptomics. Across multiple organs, SpaReg robustly reconstructs large tissue volumes with preserved subcellular morphology despite sectioning artifacts. On a standardized histology benchmark, SpaReg achieves the best balance between 3D reconstruction accuracy and tissue integrity, and on spatial transcriptomics benchmarks it ranks among the leading methods while scaling to hundreds of sections and millions of cells in a dataset that several existing methods fail to process. Preservation of subcellular morphology by SpaReg also enables training of a Hematoxylin and Eosin (H&amp;E)-based epithelial, T and B cell classifier, generating single-cell-resolved 3D maps directly from H&amp;E. Applied to pancreatic tissue containing pancreatic ductal adenocarcinoma arising from an intraductal papillary mucinous neoplasm, these maps reveal that 2D sections overestimate immune exclusion, and resolve lymphoid aggregates in 3D. SpaReg, therefore, provides a scalable foundation for morphologically faithful, multi-modal 3D atlases and spatially informed disease modeling.<\/jats:p>","DOI":"10.64898\/2026.09.28.754175","type":"posted-content","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T02:45:18Z","timestamp":1790909118000},"source":"Crossref","is-referenced-by-count":0,"title":["SpaReg: sparsity-based 3D reconstruction of tissue microenvironments at native resolution across morphological and spatial molecular modalities"],"prefix":"10.64898","author":[{"given":"Rajdeep","family":"Pawar","sequence":"first","affiliation":[{"name":"Department of Computational and Systems Biology, University of Pittsburgh"},{"name":"UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine"},{"name":"PhD Program in Cell, Molecular, and Systems Biology (CMSB), School of Medicine, University of Pittsburgh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Jacob","sequence":"additional","affiliation":[{"name":"Department of Computational and Systems Biology, University of Pittsburgh"},{"name":"UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine"},{"name":"Joint CMU-Pitt PhD Program in Computational Biology (CPCB), School of Medicine, University of Pittsburgh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Raphael","sequence":"additional","affiliation":[{"name":"UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine","family":"Byrnes","sequence":"additional","affiliation":[{"name":"UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Watkins","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Pittsburgh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T. 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