Scaling up spatial transcriptomics for large-sized tissues: uncovering cellular-level tissue architecture beyond conventional platforms with iSCALE
Recent advances in spatial transcriptomics (ST) technologies have transformed our ability to profile gene expression while preserving crucial spatial context within tissues. However, existing ST platforms are constrained by high costs, long turnaround times, low resolution, limited gene coverage and inherently small tissue capture areas, which hinder their broad applications. Here we present iSCALE, a method that reconstructs large-scale, super-resolution gene expression landscapes and automatically annotates cellular-level tissue architecture in samples exceeding capture areas of current ST platforms. The performance of iSCALE was assessed by comprehensive evaluations involving benchmarking experiments, immunohistochemistry staining and manual annotations by pathologists. When applied to multiple sclerosis human brain samples, iSCALE uncovered lesion-associated cellular characteristics undetectable by conventional ST experiments. Our results demonstrate the utility of iSCALE in analyzing large tissues by enabling unbiased annotation, resolving cell type composition, mapping cellular microenvironments and revealing spatial features beyond the reach of standard ST analysis or routine histopathological assessment.
Authors
- Hui‐Hsin Tsai
- Sarbottam Piya (ORCID: https://orcid.org/0000-0002-1070-8008)
- Amelia Schroeder
- Thomas M. Carlile (ORCID: https://orcid.org/0000-0002-7699-9354)
- Taylor L. Reynolds (ORCID: https://orcid.org/0000-0002-6941-0900)
- Tae Hyun Hwang (ORCID: https://orcid.org/0000-0002-6668-7269)
- Sicong Yao (ORCID: https://orcid.org/0009-0001-4636-6812)
- Hanying Yan (ORCID: https://orcid.org/0000-0002-9227-1742)
- Melanie Loth (ORCID: https://orcid.org/0000-0003-2717-8258)
- Daiwei Zhang (ORCID: https://orcid.org/0000-0002-5019-622X)
- Ji‐Youn Sung (ORCID: https://orcid.org/0000-0002-6607-2117)
- Jean R. Clemenceau (ORCID: https://orcid.org/0000-0002-6222-6457)
- Edward D. Plowey (ORCID: https://orcid.org/0000-0001-9016-4751)
- Inyeop Jang
- Patrick Cullen
- Minji Kim (ORCID: https://orcid.org/0009-0009-6787-0354)
- Isabel Barnfather (ORCID: https://orcid.org/0009-0007-3071-963X)
- Jeong Hwan Park (ORCID: https://orcid.org/0000-0003-4522-9928)
- Chunyu Luo (ORCID: https://orcid.org/0009-0004-7047-0857)
- Mingyao Li (ORCID: https://orcid.org/0000-0001-8180-0621)
- Baohong Zhang
- Wenxing Hu (ORCID: https://orcid.org/0000-0003-2477-6383)
- Su Jing Chan (ORCID: https://orcid.org/0000-0001-7166-9658)
Institutions
- University of North Carolina at Chapel Hill (US)
- Biogen (United States) (US)
- Seoul National University (KR)
- Seoul Metropolitan Government (KR)
- Kyung Hee University (KR)
- SNUH SMG-SNU Boramae Medical Center (KR)
- University of Pennsylvania (US)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- Nature Methods
- Published
- 2025-09-01
- DOI
- https://doi.org/10.1038/s41592-025-02770-8
- Citations
- 9
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 7.25