Reference-based cell type matching of in situ image-based spatial transcriptomics data on primary visual cortex of mouse brain

Scientific Reports, vol. 13, pp. 9567

Abstract

With the advent of multiplex fluorescence in situ hybridization (FISH) and in situ RNA sequencing technologies, spatial transcriptomics analysis is advancing rapidly, providing spatial location and gene expression information about cells in tissue sections at single cell resolution. Cell type classification of these spatially-resolved cells can be inferred by matching the spatial transcriptomics data to reference atlases derived from single cell RNA-sequencing (scRNA-seq) in which cell types are defined by differences in their gene expression profiles. However, robust cell type matching of the spatially-resolved cells to reference scRNA-seq atlases is challenging due to the intrinsic differences in resolution between the spatial and scRNA-seq data. In this study, we systematically evaluated six computational algorithms for cell type matching across four image-based spatial transcriptomics experimental protocols (MERFISH, smFISH, BaristaSeq, and ExSeq) conducted on the same mouse primary visual cortex (VISp) brain region. We find that many cells are assigned as the same type by multiple cell type matching algorithms and are present in spatial patterns previously reported from scRNA-seq studies in VISp. Furthermore, by combining the results of individual matching strategies into consensus cell type assignments, we see even greater alignment with biological expectations. We present two ensemble meta-analysis strategies used in this study and share the consensus cell type matching results in the Cytosplore Viewer ( https://viewer.cytosplore.org ) for interactive visualization and data exploration. The consensus matching can also guide spatial data analysis using SSAM, allowing segmentation-free cell type assignment.

Authors 18

1. Yun Zhang

   J. Craig Venter Institute

   Affiliation as printed

   J. Craig Venter Institute, La Jolla, CA, USA

2. Jeremy A. Miller

   Allen Institute for Brain Science

   Affiliation as printed

   Allen Institute for Brain Science, Seattle, WA, USA

3. Jeongbin Park

   Pusan National University

   Affiliation as printed

   School of Biomedical Convergence Engineering, Pusan National University, Busan, Korea

4. Boudewijn P. F. Lelieveldt Aachen Department of Radiology, Leiden University Medical Center

   Leiden University Medical Center · Delft University of Technology

   Affiliation as printed

   LKEB, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands

   Pattern Recognition and Bioinformatics Group, Delft University of Technology, Delft, The Netherlands

5. Brian Long

   Allen Institute for Brain Science

   Affiliation as printed

   Allen Institute for Brain Science, Seattle, WA, USA

6. Tamim Abdelaal Aachen Department of Radiology, Leiden University Medical Center

   Leiden University Medical Center · Delft University of Technology

   Affiliation as printed

   LKEB, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands

   Pattern Recognition and Bioinformatics Group, Delft University of Technology, Delft, The Netherlands

7. Brian D. Aevermann

   J. Craig Venter Institute · Chan Zuckerberg Initiative (United States)

   Affiliation as printed

   Chan Zuckerberg Initiative, Redwood City, CA, USA

   J. Craig Venter Institute, La Jolla, CA, USA

8. Tommaso Biancalani

   Broad Institute · Genentech

   Affiliation as printed

   Broad Institute of MIT and Harvard, Cambridge, MA, USA

   Genentech, South San Francisco, CA, USA

9. Charles S. Comiter

   Broad Institute

   Affiliation as printed

   Broad Institute of MIT and Harvard, Cambridge, MA, USA

10. Oleh Dzyubachyk Aachen Department of Radiology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    LKEB, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands

11. Jeroen Eggermont Aachen Department of Radiology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    LKEB, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands

12. Christoffer Mattsson Langseth

    Stockholm University · Science for Life Laboratory

    Affiliation as printed

    Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden

13. Viktor Petukhov

    University of Copenhagen · Harvard University

    Affiliation as printed

    Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA

14. Gabriele Scalia

    Broad Institute · Genentech

    Affiliation as printed

    Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Genentech, South San Francisco, CA, USA

15. Eeshit Dhaval Vaishnav

    Broad Institute

    Affiliation as printed

    Broad Institute of MIT and Harvard, Cambridge, MA, USA

16. Yilin Zhao

    Allen Institute for Brain Science

    Affiliation as printed

    Allen Institute for Brain Science, Seattle, WA, USA

17. Ed S. Lein

    Allen Institute for Brain Science

    Affiliation as printed

    Allen Institute for Brain Science, Seattle, WA, USA

18. Richard H. Scheuermann corresponding

    J. Craig Venter Institute · La Jolla Institute for Immunology · University of California San Diego

    Affiliation as printed

    Department of Pathology, University of California, San Diego, CA, USA. rscheuermann@jcvi.org

    Division of Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA, USA. rscheuermann@jcvi.org

    J. Craig Venter Institute, La Jolla, CA, USA. rscheuermann@jcvi.org

    Department of Pathology, University of California, San Diego, CA, USA

    Division of Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA, USA