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Recent advances in spatially resolved transcriptomics: challenges and opportunities

  • Lee, Jongwon (Department of Biomedical Sciences, Korea University College of Medicine) ;
  • Yoo, Minsu (Department of Biomedical Sciences, Korea University College of Medicine) ;
  • Choi, Jungmin (Department of Biomedical Sciences, Korea University College of Medicine)
  • Received : 2021.12.22
  • Accepted : 2022.02.11
  • Published : 2022.03.31

Abstract

Single-cell RNA sequencing (scRNA-seq) has greatly advanced our understanding of cellular heterogeneity by profiling individual cell transcriptomes. However, cell dissociation from the tissue structure causes a loss of spatial information, which hinders the identification of intercellular communication networks and global transcriptional patterns present in the tissue architecture. To overcome this limitation, novel transcriptomic platforms that preserve spatial information have been actively developed. Significant achievements in imaging technologies have enabled in situ targeted transcriptomic profiling in single cells at single-molecule resolution. In addition, technologies based on mRNA capture followed by sequencing have made possible profiling of the genome-wide transcriptome at the 55-100 ㎛ resolution. Unfortunately, neither imaging-based technology nor capture-based method elucidates a complete picture of the spatial transcriptome in a tissue. Therefore, addressing specific biological questions requires balancing experimental throughput and spatial resolution, mandating the efforts to develop computational algorithms that are pivotal to circumvent technology-specific limitations. In this review, we focus on the current state-of-the-art spatially resolved transcriptomic technologies, describe their applications in a variety of biological domains, and explore recent discoveries demonstrating their enormous potential in biomedical research. We further highlight novel integrative computational methodologies with other data modalities that provide a framework to derive biological insight into heterogeneous and complex tissue organization.

Keywords

Acknowledgement

The authors are grateful to Junho Song for critical reading of the manuscript. This research was supported by the National Research Foundation of Korea (NRF) grants funded by the South Korean government (2020R1F1A1076705).

References

  1. Hwang B, Lee JH and Bang D (2018) Single-cell RNA sequencing technologies and bioinformatics pipelines. Exp Mol Med 50, 1-14 https://doi.org/10.1038/s12276-018-0071-8
  2. Stark R, Grzelak M and Hadfield J (2019) RNA sequencing: the teenage years. Nat Rev Genet 20, 631-656 https://doi.org/10.1038/s41576-019-0150-2
  3. Roth R, Kim S, Kim J and Rhee S (2020) Single-cell and spatial transcriptomics approaches of cardiovascular development and disease. BMB Rep 53, 393-399 https://doi.org/10.5483/BMBRep.2020.53.8.130
  4. Cang Z and Nie Q (2020) Inferring spatial and signaling relationships between cells from single cell transcriptomic data. Nat Commun 11, 2084 https://doi.org/10.1038/s41467-020-15968-5
  5. Asp M, Bergenstrahle J and Lundeberg J (2020) Spatially resolved transcriptomes-next generation tools for tissue exploration. Bioessays 42, e1900221
  6. Dries R, Chen J, Del Rossi N, Khan MM, Sistig A and Yuan GC (2021) Advances in spatial transcriptomic data analysis. Genome Res 31, 1706-1718 https://doi.org/10.1101/gr.275224.121
  7. Shah S, Lubeck E, Schwarzkopf M et al (2016) Single-molecule RNA detection at depth by hybridization chain reaction and tissue hydrogel embedding and clearing. Development 143, 2862-2867 https://doi.org/10.1242/dev.138560
  8. Codeluppi S, Borm LE, Zeisel A et al (2018) Spatial organization of the somatosensory cortex revealed by osmFISH. Nat Methods 15, 932-935 https://doi.org/10.1038/s41592-018-0175-z
  9. Moffitt JR, Hao J, Wang G, Chen KH, Babcock HP and Zhuang X (2016) High-throughput single-cell gene-expression profiling with multiplexed error-robust fluorescence in situ hybridization. Proc Natl Acad Sci U S A 113, 11046-11051 https://doi.org/10.1073/pnas.1612826113
  10. Moffitt JR, Bambah-Mukku D, Eichhorn SW et al (2018) Molecular, spatial, and functional single-cell profiling of the hypothalamic preoptic region. Science 362, 6416
  11. Eng CL, Lawson M, Zhu Q et al (2019) Transcriptome-scale super-resolved imaging in tissues by RNA seqFISH. Nature 568, 235-239 https://doi.org/10.1038/s41586-019-1049-y
  12. Kishi JY, Lapan SW, Beliveau BJ et al (2019) SABER amplifies FISH: enhanced multiplexed imaging of RNA and DNA in cells and tissues. Nat Methods 16, 533-544 https://doi.org/10.1038/s41592-019-0404-0
  13. Goh JJL, Chou N, Seow WY et al (2020) Highly specific multiplexed RNA imaging in tissues with split-FISH. Nat Methods 17, 689-693 https://doi.org/10.1038/s41592-020-0858-0
  14. Borovec J, Kybic J, Arganda-Carreras I et al (2020) ANHIR: automatic non-rigid histological image registration challenge. IEEE Trans Med Imaging 39, 3042-3052 https://doi.org/10.1109/tmi.2020.2986331
  15. Wang X, Allen WE, Wright MA et al (2018) Three-dimensional intact-tissue sequencing of single-cell transcriptional states. Science 361, 6400
  16. Furth D, Hatini V and Lee JH (2019) In situ transcriptome accessibility sequencing (INSTA-seq). bioRxiv, 722819
  17. Gyllborg D, Langseth CM, Qian X et al (2020) Hybridization-based in situ sequencing (HybISS) for spatially resolved transcriptomics in human and mouse brain tissue. Nucleic Acids Res 48, e112 https://doi.org/10.1093/nar/gkaa792
  18. Qian X, Harris KD, Hauling T et al (2020) Probabilistic cell typing enables fine mapping of closely related cell types in situ. Nat Methods 17, 101-106 https://doi.org/10.1038/s41592-019-0631-4
  19. Alon S, Goodwin DR, Sinha A et al (2021) Expansion sequencing: spatially precise in situ transcriptomics in intact biological systems. Science 371, 6528
  20. Romanens L, Chaskar P, Tille JC et al (2020) Spatial transcriptomics of tumor microenvironment in formalin-fixed paraffin-embedded breast cancer. bioRxiv, 2020.2001.2031.928143
  21. Zhang X, Hu C, Huang C et al (2021) Robust acquisition of high resolution spatial transcriptomes from preserved tissues with immunofluorescence based laser capture microdissection. bioRxiv, 2021.2007.2013.452123
  22. Honda M, Oki S, Kimura R et al (2021) High-depth spatial transcriptome analysis by photo-isolation chemistry. Nat Commun 12, 4416 https://doi.org/10.1038/s41467-021-24691-8
  23. Salmen F, Stahl PL, Mollbrink A et al (2018) Barcoded solid-phase RNA capture for spatial transcriptomics profiling in mammalian tissue sections. Nat Protoc 13, 2501-2534 https://doi.org/10.1038/s41596-018-0045-2
  24. Stahl PL, Salmen F, Vickovic S et al (2016) Visualization and analysis of gene expression in tissue sections by spatial transcriptomics. Science 353, 78-82 https://doi.org/10.1126/science.aaf2403
  25. Yao Z, van Velthoven CTJ, Nguyen TN et al (2021) A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation. Cell 184, 3222-3241.e3226 https://doi.org/10.1016/j.cell.2021.04.021
  26. Wu SZ, Al-Eryani G, Roden DL et al (2021) A single-cell and spatially resolved atlas of human breast cancers. Nat Genet 53, 1334-1347 https://doi.org/10.1038/s41588-021-00911-1
  27. Fawkner-Corbett D, Antanaviciute A, Parikh K et al (2021) Spatiotemporal analysis of human intestinal development at single-cell resolution. Cell 184, 810-826.e823 https://doi.org/10.1016/j.cell.2020.12.016
  28. Chen WT, Lu A, Craessaerts K et al (2020) Spatial transcriptomics and in situ sequencing to study Alzheimer's Disease. Cell 182, 976-991.e919 https://doi.org/10.1016/j.cell.2020.06.038
  29. Ji AL, Rubin AJ, Thrane K et al (2020) Multimodal analysis of composition and spatial architecture in human squamous cell carcinoma. Cell 182, 497-514.e422 https://doi.org/10.1016/j.cell.2020.05.039
  30. Rodriques SG, Stickels RR, Goeva A et al (2019) Slide-seq: A scalable technology for measuring genome-wide expression at high spatial resolution. Science 363, 1463-1467 https://doi.org/10.1126/science.aaw1219
  31. Vickovic S, Eraslan G, Salmen F et al (2019) High-definition spatial transcriptomics for in situ tissue profiling. Nat Methods 16, 987-990 https://doi.org/10.1038/s41592-019-0548-y
  32. Stickels RR, Murray E, Kumar P et al (2021) Highly sensitive spatial transcriptomics at near-cellular resolution with Slide-seqV2. Nat Biotechnol 39, 313-319 https://doi.org/10.1038/s41587-020-0739-1
  33. Cho CS, Xi J, Si Y et al (2021) Microscopic examination of spatial transcriptome using Seq-Scope. Cell 184, 3559-3572. e3522 https://doi.org/10.1016/j.cell.2021.05.010
  34. Chen A, Liao S, Cheng M et al (2021) Spatiotemporal transcriptomic atlas of mouse organogenesis using DNA nanoball patterned arrays. bioRxiv, 2021.2001.2017.427004
  35. Lohoff T, Ghazanfar S, Missarova A et al (2022) Integration of spatial and single-cell transcriptomic data elucidates mouse organogenesis. Nat Biotechnol 40, 74-85 https://doi.org/10.1038/s41587-021-01006-2
  36. Moncada R, Barkley D, Wagner F et al (2020) Integrating microarray-based spatial transcriptomics and single-cell RNA-seq reveals tissue architecture in pancreatic ductal adenocarcinomas. Nat Biotechnol 38, 333-342 https://doi.org/10.1038/s41587-019-0392-8
  37. Maseda F, Cang Z and Nie Q (2021) DEEPsc: a deep learning-based map connecting single-cell transcriptomics and spatial imaging data. Front Genet 12, 636743 https://doi.org/10.3389/fgene.2021.636743
  38. Zhao E, Stone MR, Ren X et al (2021) Spatial transcriptomics at subspot resolution with BayesSpace. Nat Biotechnol 39, 1375-1384 https://doi.org/10.1038/s41587-021-00935-2
  39. Chidester B, Zhou T and Ma J (2021) SPICEMIX: integrative single-cell spatial modeling for inferring cell identity. bioRxiv, 2020.2011.2029.383067
  40. Cable DM, Murray E, Zou LS et al (2021) Robust decomposition of cell type mixtures in spatial transcriptomics. Nat Biotechnol [Epub ahead of print]
  41. Elosua-Bayes M, Nieto P, Mereu E, Gut I and Heyn H (2021) SPOTlight: seeded NMF regression to deconvolute spatial transcriptomics spots with single-cell transcriptomes. Nucleic Acids Res 49, e50 https://doi.org/10.1093/nar/gkab043
  42. Dong R and Yuan GC (2021) SpatialDWLS: accurate deconvolution of spatial transcriptomic data. Genome Biol 22, 145 https://doi.org/10.1186/s13059-021-02362-7
  43. Lopez R, Li B, Keren-Shaul H et al (2021) Multi-resolution deconvolution of spatial transcriptomics data reveals continuous patterns of inflammation. bioRxiv, 2021.2005.2010.443517
  44. He B, Bergenstrahle L, Stenbeck L et al (2020) Integrating spatial gene expression and breast tumour morphology via deep learning. Nat Biomed Eng 4, 827-834 https://doi.org/10.1038/s41551-020-0578-x
  45. Pang M, Su K and Li M (2021) Leveraging information in spatial transcriptomics to predict super-resolution gene expression from histology images in tumors. bioRxiv, 2021.2011.2028.470212
  46. Pham D, Tan X, Xu J et al (2020) stLearn: integrating spatial location, tissue morphology and gene expression to find cell types, cell-cell interactions and spatial trajectories within undissociated tissues. bioRxiv, 2020.2005.2031.125658
  47. Tan X, Su A, Tran M and Nguyen Q (2020) SpaCell: integrating tissue morphology and spatial gene expression to predict disease cells. Bioinformatics 36, 2293-2294 https://doi.org/10.1093/bioinformatics/btz914
  48. Xu W, Gao Y, Wang Y and Guan J (2021) Protein-protein interaction prediction based on ordinal regression and recurrent convolutional neural networks. BMC Bioinformatics 22, 485 https://doi.org/10.1186/s12859-021-04369-0
  49. Bergenstrahle J, Larsson L and Lundeberg J (2020) Seamless integration of image and molecular analysis for spatial transcriptomics workflows. BMC Genomics 21, 482 https://doi.org/10.1186/s12864-020-06832-3
  50. Bergenstrahle L, He B, Bergenstrahle J et al (2020) Super-resolved spatial transcriptomics by deep data fusion. bioRxiv, 2020.2002.2028.963413
  51. Kelly RT (2020) Single-cell proteomics: progress and prospects. Mol Cell Proteomics 19, 1739-1748 https://doi.org/10.1074/mcp.R120.002234
  52. Stoeckius M, Hafemeister C, Stephenson W et al (2017) Simultaneous epitope and transcriptome measurement in single cells. Nat Methods 14, 865-868 https://doi.org/10.1038/nmeth.4380
  53. Schulz D, Zanotelli VRT, Fischer JR et al (2018) Simultaneous multiplexed imaging of mRNA and proteins with subcellular resolution in breast cancer tissue samples by mass cytometry. Cell Syst 6, 25-36.e25 https://doi.org/10.1016/j.cels.2017.12.001
  54. Piehowski PD, Zhu Y, Bramer LM et al (2020) Automated mass spectrometry imaging of over 2000 proteins from tissue sections at 100-㎛ spatial resolution. Nat Commun 11, 8 https://doi.org/10.1038/s41467-019-13858-z
  55. Thornton CA, Mulqueen RM, Torkenczy KA et al (2021) Spatially mapped single-cell chromatin accessibility. Nat Commun 12, 1274 https://doi.org/10.1038/s41467-021-21515-7
  56. Deng Y, Bartosovic M, Ma S et al (2021) Spatial-ATAC-seq: spatially resolved chromatin accessibility profiling of tissues at genome scale and cellular level. bioRxiv, 2021.2006.2006.447244