Cited by 219Single-cell and spatial transcriptomicsCell Image Analysis TechniquesGene expression and cancer classification

Inferring super-resolution tissue architecture by integrating spatial transcriptomics with histology

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Zhang, Daiwei, Schroeder, Amelia, Yan, Hanying, Yang, Haochen, Hu, Jian, Lee, Michelle Y. Y., Cho, Kyung S., Susztak, Katalin +6 more·2024·Nature Biotechnology

Abstract

Spatial transcriptomics (ST) has demonstrated enormous potential for generating intricate molecular maps of cells within tissues. Here we present iStar, a method based on hierarchical image feature extraction that integrates ST data and high-resolution histology images to predict spatial gene expression with super-resolution. Our method enhances gene expression resolution to near-single-cell levels in ST and enables gene expression prediction in tissue sections where only histology images are available.

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Crossref · 10.1038/s41587-023-02019-9

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  • Some deep learning approaches have focused on detecting molecular alterations in image data, while most existing studies have centered on inferring spatial transcriptome or bulk transcriptome information from histopathology images.

    “While some deep learning approaches have focused on detecting molecular alterations in image data [132], most existing studies have centered on inferring spatial transcriptome or bulk transcriptome information from histopathology images [133–136].”

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Research works printed but not linked: 40

  1. [1]Burgess DJ Spatial transcriptomics coming of age. Nat. Rev. Genet 20, 317 (2019). 30980030
  2. [2]Asp M, Bergenstrahle J. & Lundeberg J. Spatially Resolved Transcriptomes-Next Generation Tools for Tissue Exploration. Bioessays 42, e1900221 (2020). 32363691
  3. [4]Moor AE & Itzkovitz S. Spatial transcriptomics: paving the way for tissue-level systems biology. Curr. Opin. Biotechnol 46, 126– 133 (2017). 28346891
  4. [6]Sun S, Zhu J. & Zhou X. Statistical analysis of spatial expression patterns for spatially resolved transcriptomic studies. Nat. Methods 17, 193– 200 (2020). 31988518 PMC7233129
  5. [8]Dries R. Giotto: a toolbox for integrative analysis and visualization of spatial expression data. Genome Biol. 22, 78 (2021). 33685491 PMC7938609
  6. [9]Pham D. stLearn: integrating spatial location, tissue morphology and gene expression to find cell types, cell-cell interactions and spatial trajectories within undissociated tissues. Preprint at bioRxiv, 10.1101/2020.05.31.125658 (2020). · DOI
  7. [10]Asp M. A Spatiotemporal Organ-Wide Gene Expression and Cell Atlas of the Developing Human Heart. Cell 179, 1647– 1660 e1619 (2019). 31835037
  8. [12]Lubeck E, Coskun AF, Zhiyentayev T, Ahmad M. & Cai L. Single-cell in situ RNA profiling by sequential hybridization. Nat. Methods 11, 360– 361 (2014). 24681720 PMC4085791
  9. [13]Shah S, Lubeck E, Zhou W. & Cai L. In Situ Transcription Profiling of Single Cells Reveals Spatial Organization of Cells in the Mouse Hippocampus. Neuron 92, 342– 357 (2016). 27764670 PMC5087994
  10. [14]Eng CL Transcriptome-scale super-resolved imaging in tissues by RNA seqFISH. Nature 568, 235– 239 (2019). 30911168 PMC6544023
  11. [15]Moffitt JR Molecular, spatial, and functional single-cell profiling of the hypothalamic preoptic region. Science 362, eaau5324 (2018). PMC6482113 30385464
  12. [16]Chen KH, Boettiger AN, Moffitt JR, Wang S. & Zhuang X. RNA imaging. Spatially resolved, highly multiplexed RNA profiling in single cells. Science 348, aaa6090 (2015). PMC4662681 25858977
  13. [19]Badea L. & Stanescu E. Identifying transcriptomic correlates of histology using deep learning. PLoS One 15, e0242858 (2020). PMC7688140 33237966
  14. [20]Ash JT, Darnell G, Munro D. & Engelhardt BE Joint analysis of expression levels and histological images identifies genes associated with tissue morphology. Nat. Commun 12, 1609 (2021). 33707455 PMC7952575
  15. [21]Schmauch B. A deep learning model to predict RNA-Seq expression of tumours from whole slide images. Nat. Commun 11, 3877 (2020). 32747659 PMC7400514
  16. [22]Chen RJ Scaling vision transformers to gigapixel images via hierarchical self-supervised learning. Proceedings of the IEEE/CVF Conference on Computer Vision and Pattern Recognition, 16144– 16155 (2022).
  17. [26]Bao H, Dong L, Piao S. & Wei F. Beit: Bert pre-training of image transformers. Preprint at arXiv, 10.48550/arXiv.2106.08254 (2021). · DOI · Paper page
  18. [27]Janesick A. High resolution mapping of the breast cancer tumor microenvironment using integrated single cell, spatial and in situ analysis of FFPE tissue. Preprint at bioRxiv, 10.1101/2022.10.06.510405 (2022). PMC10730913 38114474 · DOI
  19. [28]Bergenstråhle L. Super-resolved spatial transcriptomics by deep data fusion. Nat. biotechnol 40, 476– 479 (2022). 34845373
  20. [30]Hamerly G. & Elkan C. Learning the k in k-means. Advances in neural information processing systems 16 (2003).
  21. [31]Andersson A. Spatial deconvolution of HER2-positive breast cancer delineates tumor-associated cell type interactions. Nat. Commun 12, 6012 (2021). 34650042 PMC8516894
  22. [33]Wu SZ A single-cell and spatially resolved atlas of human breast cancers. Nat. genetics 53, 1334– 1347 (2021). 34493872 PMC9044823
  23. [35]Fridman WH B cells and tertiary lymphoid structures as determinants of tumour immune contexture and clinical outcome. Nat. Rev. Clin. Oncol 19, 441– 457 (2022). 35365796
  24. [38]Cabrita R. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature 577, 561– 565 (2020). 31942071
  25. [39]Lin JR Multiplexed 3D atlas of state transitions and immune interaction in colorectal cancer. Cell 186, 363– 381 e319 (2023). 36669472 PMC10019067
  26. [40]Steiner A. How to train your vit? data, augmentation, and regularization in vision transformers. Preprint at arXiv, 10.48550/arXiv.2106.10270 (2021). · DOI · Paper page
  27. [41]Hölscher DL Next-Generation Morphometry for pathomics-data mining in histopathology. Nat. Commun 14, 470 (2023). 36709324 PMC9884209
  28. [42]Rappez L. SpaceM reveals metabolic states of single cells. Nat. Methods 18, 799– 805 (2021). 34226721 PMC7611214
  29. [43]Xu B, Wang N, Chen T. & Li M. Empirical evaluation of rectified activations in convolutional network. Preprint arXiv, 10.48550/arXiv.1505.00853 (2015). · DOI · Paper page
  30. [44]Clevert D-A, Unterthiner T. & Hochreiter S. Fast and accurate deep network learning by exponential linear units (ELUs). Preprint at arXiv, 10.48550/arXiv.1511.07289 (2015). · DOI · Paper page
  31. [46]McInnes L, Healy J. & Melville J. Umap: Uniform manifold approximation and projection for dimension reduction. Preprint at arXiv, 10.48550/arXiv.1802.03426 (2018). · DOI · Paper page
  32. [47]Schurch CM Coordinated Cellular Neighborhoods Orchestrate Antitumoral Immunity at the Colorectal Cancer Invasive Front. Cell 182, 1341– 1359 e1319 (2020). 32763154 PMC7479520
  33. [49]Hu J. Iterative transfer learning with neural network for clustering and cell type classification in single-cell RNA-seq analysis. Nat machine intelligence 2, 607– 618 (2020). PMC8009055 33817554
  34. [50]Lu Y. The level weighted structural similarity loss: A step away from MSE. Proceedings of the AAAI Conference on Artificial Intelligence 33, 9989– 9990 (2019).
  35. [51]Lai W-S, Huang J-B, Ahuja N. & Yang M-H Deep laplacian pyramid networks for fast and accurate super-resolution. Proceedings of the IEEE conference on computer vision and pattern recognition, 624– 632 (2017).
  36. [52]Dahl R, Norouzi M. & Shlens J. Pixel recursive super resolution. Proceedings of the IEEE international conference on computer vision, 5439– 5448 (2017).
  37. [53]Masutani EM, Bahrami N. & Hsiao A. Deep learning single-frame and multiframe super-resolution for cardiac MRI. Radiology 295, 552– 561 (2020). 32286192 PMC7263289
  38. [54]Anwar S, Khan S. & Barnes N. A deep journey into super-resolution: A survey. ACM Computing Surveys (CSUR) 53, 1– 34 (2020).
  39. [55]Wang Z, Chen J. & Hoi SC Deep learning for image super-resolution: A survey. IEEE transactions on pattern analysis and machine intelligence 43, 3365– 3387 (2020). 32217470
  40. [56]Ma Y. & Zhou X. Spatially informed cell-type deconvolution for spatial transcriptomics. Nat. Biotechnol 40, 1349– 1359 (2022). 35501392 PMC9464662

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Authors
Zhang, D., Schroeder, A., Yan, H., Yang, H., Hu, J., Lee, M. Y. Y., Cho, K. S., Susztak, K., Xu, G. X., Feldman, M. D., Lee, E. B., Furth, E. E., Wang, L., & Li, M.
Affiliations
  • University of Pennsylvania (US)
  • Emory University (US)
  • The University of Texas MD Anderson Cancer Center (US)
  • Indiana University Indianapolis (US)
Corresponding author
  • Zhang, Daiwei
  • Li, Mingyao
Venue
Nature Biotechnology
Published
2024-01-02
Volume
42
Issue
9
Pages
1372-1377
ISSN
  • 0733-222X (ISSN-L)
  • 1087-0156
  • 1546-1696
OpenAlex
W4390500930
Cited by
219
References
16
Citations by year
2026: 93 · 2025: 73 · 2024: 53
FWCI
29.81
Type
journal article
Language
en
Open access
Locations
  • Nature Biotechnology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (R01GM125301)
  • U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (R01HL150359)
  • U.S. Department of Health & Human Services | NIH | National Eye Institute (R01EY030192)
  • U.S. Department of Health & Human Services | NIH | National Institute on Aging (P01AG066597)
  • U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (R01HG013158)
  • U.S. Department of Health & Human Services | NIH | National Cancer Institute (R01CA266280, U01CA264583)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Cell Image Analysis Techniques
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene expression and cancer classification
Keywords
spatial transcriptomics, histology, tissue structure, gene expression prediction, ISTAR, single-cell resolution, tissue sections
MeSH terms
Algorithms, Animals, Humans, Image Processing, Computer-Assisted, Gene Expression Profiling, Single-Cell Analysis, Transcriptome

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