Super-resolved spatial transcriptomics by deep data fusion
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Abstract
Current methods for spatial transcriptomics are limited by low spatial resolution. Here we introduce a method that integrates spatial gene expression data with histological image data from the same tissue section to infer higher-resolution expression maps. Using a deep generative model, our method characterizes the transcriptome of micrometer-scale anatomical features and can predict spatial gene expression from histology images alone.
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Researchers have utilized deep learning to leverage histopathology images to predict spatial gene expression from these images alone, pointing to morphological features not captured by human experts that could potentially enhance utility and lower costs.
“Of note, researchers have utilized deep learning to leverage histopathology images to predict spatial gene expression from these images alone, pointing to morphological features in these images not captured by human experts that could potentially enhance the utility and lower the costs of this technology 25,26 .”
From Multimodal biomedical AI (2022) · cites this paper as [26]
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Cites
U-Net: Convolutional Networks for Biomedical Image Segmentation
Ronneberger, O., Fischer, P., & Brox, T. (2015) · Lecture notes in computer science · doi:10.1007/978-3-319-24574-4_28 · Cited by 99,404 · see citing works
Adam: A Method for Stochastic Optimization
Kingma, D. P., & Ba, J. (2014) · arXiv · doi:10.48550/arxiv.1412.6980 · Cited by 98,946 · see citing works
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
Love, M. I., Huber, W., & Anders, S. (2014) · Genome Biology · doi:10.1186/s13059-014-0550-8 · Cited by 95,106 · see citing works
Gene Ontology: tool for the unification of biology
Ashburner, M., Ball, C. A., Blake, J. A., Botstein, D., Butler, H., Cherry, J. M., Davis, A. P., Dolinski, K., Dwight, S. S., Eppig, J. T., et al. (2000) · Nature Genetics · doi:10.1038/75556 · Cited by 43,206 · see citing works
PyTorch: An Imperative Style, High-Performance Deep Learning Library
Paszke, A., Gross, S., Massa, F., Lerer, A., Bradbury, J., Chanan, G., Killeen, T., Lin, Z., Gimelshein, N., Antiga, L., et al. (2019) · arXiv · doi:10.48550/arxiv.1912.01703 · Cited by 31,473 · see citing works
Auto-Encoding Variational Bayes
Kingma, D. P., & Welling, M. (2013) · arXiv · doi:10.48550/arxiv.1312.6114 · Cited by 20,067 · see citing works
Tissue-based map of the human proteome
Uhlén, M., Fagerberg, L., Hallström, B. M., Lindskog, C., Oksvold, P., Mardinoglu, A., Sivertsson, Å., Kampf, C., Sjöstedt, E., Asplund, A., et al. (2015) · Science · doi:10.1126/science.1260419 · Cited by 15,286 · see citing works
Integrating single-cell transcriptomic data across different conditions, technologies, and species
Butler, A., Hoffman, P., Smibert, P., Papalexi, E., & Satija, R. (2018) · Nature Biotechnology · doi:10.1038/nbt.4096 · Cited by 13,174 · see citing works
Spatial reconstruction of single-cell gene expression data
Satija, R., Farrell, J. A., Gennert, D., Schier, A. F., & Regev, A. (2015) · Nature Biotechnology · doi:10.1038/nbt.3192 · Cited by 7,055 · see citing works
Genome-wide atlas of gene expression in the adult mouse brain
Lein, E. S., Hawrylycz, M. J., Ao, N., Ayres, M., Bensinger, A., Bernard, A., Boe, A. F., Boguski, M. S., Brockway, K. S., Byrnes, E. J., et al. (2007) · Nature · doi:10.1038/nature05453 · Cited by 5,572 · see citing works
Raudvere, U., Kolberg, L., Kuzmin, I., Arak, T., Adler, P., Peterson, H., & Vilo, J. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz369 · Cited by 5,045 · see citing works
The Gene Ontology Resource: 20 years and still GOing strong
The Gene Ontology Consortium (2019) · Nucleic Acids Research · doi:10.1093/nar/gky1055 · Cited by 4,747 · see citing works
Variational Inference: A Review for Statisticians
Blei, D. M., Kucukelbir, A., & McAuliffe, J. D. (2017) · Journal of the American Statistical Association · doi:10.1080/01621459.2017.1285773 · Cited by 3,974 · see citing works
Visualization and analysis of gene expression in tissue sections by spatial transcriptomics
Ståhl, P. L., Salmén, F., Vickovic, S., Lundmark, A., Navarro, J. F., Magnusson, J., Giacomello, S., Asp, M., Westholm, J. O., Huss, M., et al. (2016) · Science · doi:10.1126/science.aaf2403 · Cited by 3,834 · see citing works
Self-citationStochastic Backpropagation and Approximate Inference in Deep Generative ModelsPreprint
Rezende, D. J., Mohamed, S., & Wierstra, D. (2014) · arXiv (Cornell University) · doi:10.48550/arxiv.1401.4082 · Cited by 3,679 · see citing works
Spatially resolved, highly multiplexed RNA profiling in single cells
Chen, K. H., Boettiger, A. N., Moffitt, J. R., Wang, S., & Zhuang, X. (2015) · Science · doi:10.1126/science.aaa6090 · Cited by 2,969 · see citing works
Deep generative modeling for single-cell transcriptomics
Lopez, R., Regier, J., Cole, M. B., Jordan, M. I., & Yosef, N. (2018) · Nature Methods · doi:10.1038/s41592-018-0229-2 · Cited by 2,530 · see citing works
Slide-seq: A scalable technology for measuring genome-wide expression at high spatial resolution
Rodriques, S. G., Stickels, R. R., Goeva, A., Martin, C. A., Murray, E., Vanderburg, C. R., Welch, J., Chen, L. M., Chen, F., & Macosko, E. Z. (2019) · Science · doi:10.1126/science.aaw1219 · Cited by 2,424 · see citing works
Variational Inference: A Review for Statisticians
Blei, D. M., Kucukelbir, A., & McAuliffe, J. (2023) · Figshare · doi:10.6084/m9.figshare.5203696.v2 · Cited by 2,088 · see citing works
A single-cell and spatially resolved atlas of human breast cancers
Wu, S. Z., Al-Eryani, G., Roden, D. L., Junankar, S., Harvey, K., Andersson, A., Thennavan, A., Wang, C., Torpy, J. R., Bartonicek, N., et al. (2021) · Nature Genetics · doi:10.1038/s41588-021-00911-1 · Cited by 1,775 · see citing works
Self-citationTranscriptome-scale super-resolved imaging in tissues by RNA seqFISH
Eng, C.-H. L., Lawson, M., Zhu, Q., Dries, R., Koulena, N., Takei, Y., Yun, J., Cronin, C., Karp, C., Yuan, G.-C., et al. (2019) · Nature · doi:10.1038/s41586-019-1049-y · Cited by 1,754 · see citing works
Visualization of Single RNA Transcripts in Situ
Femino, A. M., Fay, F. S., Fogarty, K., & Singer, R. H. (1998) · Science · doi:10.1126/science.280.5363.585 · Cited by 1,504 · see citing works
Robust decomposition of cell type mixtures in spatial transcriptomics
Cable, D. M., Murray, E., Zou, L. S., Goeva, A., Macosko, E. Z., Chen, F., & Irizarry, R. A. (2022) · Nature Biotechnology · doi:10.1038/s41587-021-00830-w · Cited by 1,487 · see citing works
A method for normalizing histology slides for quantitative analysis
Macenko, M., Niethammer, M., Marron, J. S., Borland, D., Woosley, J. T., Guan, X., Schmitt, C., & Thomas, N. E. (2009) · 2009 IEEE International Symposium on Biomedical Imaging: From Nano to Macro · doi:10.1109/isbi.2009.5193250 · Cited by 1,482 · see citing works
Highly sensitive spatial transcriptomics at near-cellular resolution with Slide-seqV2
Stickels, R. R., Murray, E., Kumar, P., Li, J., Marshall, J. L., Di Bella, D. J., Arlotta, P., Macosko, E. Z., & Chen, F. (2021) · Nature Biotechnology · doi:10.1038/s41587-020-0739-1 · Cited by 1,295 · see citing works
High-definition spatial transcriptomics for in situ tissue profiling
Vickovic, S., Eraslan, G., Salmén, F., Klughammer, J., Stenbeck, L., Schapiro, D., Äijö, T., Bonneau, R., Bergenstråhle, L., Navarro, J. F., et al. (2019) · Nature Methods · doi:10.1038/s41592-019-0548-y · Cited by 1,150 · see citing works
Self-citationMultimodal Analysis of Composition and Spatial Architecture in Human Squamous Cell Carcinoma
Ji, A. L., Rubin, A. J., Thrane, K., Jiang, S., Reynolds, D. L., Meyers, R. M., Guo, M. G., George, B. M., Mollbrink, A., Bergenstråhle, J., et al. (2020) · Cell · doi:10.1016/j.cell.2020.05.039 · Cited by 1,117 · cited 1× · see citing works
“25 .”
Self-citationSingle-cell RNA-seq denoising using a deep count autoencoder
Eraslan, G., Simon, L. M., Mircea, M., Mueller, N. S., & Theis, F. J. (2019) · Nature Communications · doi:10.1038/s41467-018-07931-2 · Cited by 1,084 · see citing works
Moncada, R., Barkley, D., Wagner, F., Chiodin, M., Devlin, J. C., Baron, M., Hajdu, C. H., Simeone, D. M., & Yanai, I. (2020) · Nature Biotechnology · doi:10.1038/s41587-019-0392-8 · Cited by 1,045 · see citing works
Highly Multiplexed Subcellular RNA Sequencing in Situ
Lee, J. H., Daugharthy, E. R., Scheiman, J., Kalhor, R., Yang, J. L., Ferrante, T. C., Terry, R., Jeanty, S. S. F., Li, C., Amamoto, R., et al. (2014) · Science · doi:10.1126/science.1250212 · Cited by 973 · see citing works
High-Spatial-Resolution Multi-Omics Sequencing via Deterministic Barcoding in Tissue
Liu, Y., Yang, M., Deng, Y., Su, G., Enninful, A., Guo, C. C., Tebaldi, T., Zhang, D., Kim, D., Bai, Z., et al. (2020) · Cell · doi:10.1016/j.cell.2020.10.026 · Cited by 966 · see citing works
In situ sequencing for RNA analysis in preserved tissue and cells
Ke, R., Mignardi, M., Pacureanu, A., Svedlund, J., Botling, J., Wählby, C., & Nilsson, M. (2013) · Nature Methods · doi:10.1038/nmeth.2563 · Cited by 934 · see citing works
Pyro: Deep Universal Probabilistic ProgrammingPreprint
Bingham, E., Chen, J. P., Jankowiak, M., Obermeyer, F. H., Pradhan, N., Karaletsos, T., Singh, R., Szerlip, P., Horsfall, P., & Goodman, N. D. (2018) · arXiv (Cornell University) · doi:10.48550/arxiv.1810.09538 · Cited by 767 · see citing works
A Spatiotemporal Organ-Wide Gene Expression and Cell Atlas of the Developing Human Heart
Asp, M., Giacomello, S., Larsson, L., Wu, C., Fürth, D., Qian, X., Wärdell, E., Custodio, J., Reimegård, J., Salmén, F., et al. (2019) · Cell · doi:10.1016/j.cell.2019.11.025 · Cited by 740 · see citing works
Self-citationElosua-Bayes, M., Nieto, P., Mereu, E., Gut, I., & Heyn, H. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab043 · Cited by 732 · see citing works
SpatialDE: identification of spatially variable genes
Svensson, V., Teichmann, S. A., & Stegle, O. (2018) · Nature Methods · doi:10.1038/nmeth.4636 · Cited by 695 · see citing works
Shah, S., Lubeck, E., Zhou, W., & Cai, L. (2016) · Neuron · doi:10.1016/j.neuron.2016.10.001 · Cited by 671 · see citing works
Medical Image Computing and Computer-Assisted Intervention – MICCAI 2015
Navab, N., Joachim Hornegger, A., Wells, W. M., & Frangi, A. F. (2015) · Lecture notes in computer science · doi:10.1007/978-3-319-24574-4 · Cited by 545 · see citing works
Statistical analysis of spatial expression patterns for spatially resolved transcriptomic studies
Sun, S., Zhu, J., & Zhou, X. (2020) · Nature Methods · doi:10.1038/s41592-019-0701-7 · Cited by 502 · see citing works
Single-cell and spatial transcriptomics enables probabilistic inference of cell type topography
Andersson, A., Bergenstråhle, J., Asp, M., Bergenstråhle, L., Jurek, A., Navarro, J. F., & Lundeberg, J. (2020) · Communications Biology · doi:10.1038/s42003-020-01247-y · Cited by 463 · see citing works
Self-citationHigh-throughput spatial mapping of single-cell RNA-seq data to tissue of origin
Achim, K., Pettit, J.-B., Saraiva, L. R., Gavriouchkina, D., Larsson, T., Arendt, D., & Marioni, J. C. (2015) · Nature Biotechnology · doi:10.1038/nbt.3209 · Cited by 395 · see citing works
Bulla, R., Tripodo, C., Rami, D., Ling, G. S., Agostinis, C., Guarnotta, C., Zorzet, S., Durigutto, P., Botto, M., & Tedesco, F. (2016) · Nature Communications · doi:10.1038/ncomms10346 · Cited by 295 · see citing works
Nitzan, M., Karaiskos, N., Friedman, N., & Rajewsky, N. (2019) · Nature · doi:10.1038/s41586-019-1773-3 · Cited by 272 · see citing works
Probabilistic cell typing enables fine mapping of closely related cell types in situ
Qian, X., Harris, K. D., Hauling, T., Nicoloutsopoulos, D., Muñoz‐Manchado, A. B., Skene, N., Hjerling‐Leffler, J., & Nilsson, M. F. (2019) · Nature Methods · doi:10.1038/s41592-019-0631-4 · Cited by 230 · see citing works
Multimodal Analysis of Composition and Spatial Architecture in Human Squamous Cell Carcinoma
Ji, A. L., Rubin, A. J., Thrane, K., Jiang, S., Reynolds, D. L., Meyers, R. M., Guo, M. G., George, B. M., Mollbrink, A., Bergenstråhle, J., et al. (2020) · Cell · doi:10.1016/j.cell.2020.08.043 · Cited by 215 · see citing works
Self-citationTepe, B., Hill, M. C., Pekarek, B. T., Hunt, P. J., Martin, T. J., Martin, J. F., & Arenkiel, B. R. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.11.034 · Cited by 183 · see citing works
Lopez, R., Nazaret, A., Langevin, M., Samaran, J., Regier, J., Jordan, M. I., & Yosef, N. (2019) · arXiv · doi:10.48550/arxiv.1905.02269 · Cited by 105 · see citing works
Metodieva, G., Nogueira-de-Souza, N. C., Greenwood, C., Al-Janabi, K., Leng, L., Bucala, R., & Metodiev, M. V. (2013) · Neoplasia · doi:10.1593/neo.13464 · Cited by 40 · see citing works
Decontamination of Mutual Contamination ModelsPreprint
Katz-Samuels, J., Blanchard, G., & Scott, C. D. (2017) · arXiv (Cornell University) · doi:10.48550/arxiv.1710.01167 · Cited by 16 · see citing works
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Scientific discovery in the age of artificial intelligence.
Wang, H., Fu, T., Du, Y., Gao, W., Huang, K., Liu, Z., Chandak, P., Liu, S., Van Katwyk, P., Deac, A., et al. (2023) · Nature · doi:10.1038/s41586-023-06221-2 · Cited by 1,823 · see citing works
“Deep convolutional methods, which utilize algorithmic advances such as spectral deconvolution 54,55 , flexible sparsity 52 and generative capability 56 , can transform poor spatiotemporally resolved measurements into high-quality, super-resolved and structured images.”
MethodExploring tissue architecture using spatial transcriptomics
Rao, A., Barkley, D., França, G. S., & Yanai, I. (2021) · Nature · doi:10.1038/s41586-021-03634-9 · Cited by 1,700 · see citing works
Acosta, J. N., Falcone, G. J., Rajpurkar, P., & Topol, E. J. (2022) · Nature Medicine · doi:10.1038/s41591-022-01981-2 · Cited by 1,365 · see citing works
Methods and applications for single-cell and spatial multi-omics
Vandereyken, K., Sifrim, A., Thienpont, B., & Voet, T. (2023) · Nature Reviews Genetics · doi:10.1038/s41576-023-00580-2 · Cited by 1,244 · see citing works
Best practices for single-cell analysis across modalities
Heumos, L., Schaar, A. C., Lance, C., Litinetskaya, A., Drost, F., Zappia, L., Lücken, M. D., Strobl, D. C., Henao, J., Curion, F., et al. (2023) · Nature Reviews Genetics · doi:10.1038/s41576-023-00586-w · Cited by 1,051 · see citing works
“Tangram 224 , GridNet 230 and eggplant 231 generate common coordinate frameworks across samples to mitigate this issue 232 .”
BackgroundIntegrating single-cell and spatial transcriptomics to elucidate intercellular tissue dynamics
Longo, S. K., Guo, M. G., Ji, A. L., & Khavari, P. A. (2021) · Nature Reviews Genetics · doi:10.1038/s41576-021-00370-8 · Cited by 1,059 · see citing works
Self-citationSpatially resolved transcriptomes—next generation tools for tissue exploration
Asp, M., Bergenstråhle, J., & Lundeberg, J. (2020) · BioEssays · doi:10.1002/bies.201900221 · Cited by 666 · see citing works
Self-citationStatistical and machine learning methods for spatially resolved transcriptomics data analysis
Zeng, Z., Li, Y., Li, Y., & Luo, Y. (2022) · Genome Biology · doi:10.1186/s13059-022-02653-7 · Cited by 186 · see citing works
Novel research and future prospects of artificial intelligence in cancer diagnosis and treatment
Zhang, C., Xu, J., Tang, R., Yang, J., Wang, W., Yu, X., & Shi, S. (2023) · Journal of Hematology & Oncology · doi:10.1186/s13045-023-01514-5 · Cited by 148 · see citing works
Advancing biological understanding of cellular senescence with computational multiomics
Li, S., Agudelo Garcia, P. A., Aliferis, C., Becich, M. J., Calyeca, J., Cosgrove, B. D., Elisseeff, J., Farzad, N., Fertig, E. J., Glass, C., et al. (2025) · Nature Genetics · doi:10.1038/s41588-025-02314-y · Cited by 40 · see citing works
- Authors
- Bergenstråhle, L., He, B., Bergenstråhle, J., Abalo, X., Mirzazadeh, R., Thrane, K., Ji, A. L., Andersson, A., Larsson, L., Stakenborg, N., Boeckxstaens, G., Khavari, P., Zou, J., Lundeberg, J., & Maaskola, J.
- Affiliations
- Science for Life Laboratory (SE)
- Stanford University (US)
- Stanford Cancer Institute (US)
- KU Leuven (BE)
- Stockholm University (SE)
- Corresponding author
- Lundeberg, Joakim
- ORCID
- Venue
- Nature Biotechnology
- Published
- 2021-11-29
- Volume
- 40
- Issue
- 4
- Pages
- 476-479
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- OpenAlex
- W3217269355
- Cited by
- 188
- References
- 49
- Citations by year
- 2026: 38 · 2025: 44 · 2024: 43 · 2023: 25 · 2022: 22 · 2021: 14 · 2020: 2
- FWCI
- 8.63
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Biotechnology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- Funders
- Knut och Alice Wallenbergs Stiftelse (NA)
- Familjen Erling-Perssons Stiftelse (NA)
- Cancerfonden (NA)
- Stiftelsen för Strategisk Forskning (NA)
- Vetenskapsrådet (NA)
- Leona M. and Harry B. Helmsley Charitable Trust (NA)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene expression and cancer classification
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Keywords
- spatial transcriptomics, super-resolution, histological images, spatial gene expression, deep generative models, tissue sections
- MeSH terms
- Transcriptome
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