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      Single-cell and spatial transcriptomics enables probabilistic inference of cell type topography

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          Abstract

          The field of spatial transcriptomics is rapidly expanding, and with it the repertoire of available technologies. However, several of the transcriptome-wide spatial assays do not operate on a single cell level, but rather produce data comprised of contributions from a – potentially heterogeneous – mixture of cells. Still, these techniques are attractive to use when examining complex tissue specimens with diverse cell populations, where complete expression profiles are required to properly capture their richness. Motivated by an interest to put gene expression into context and delineate the spatial arrangement of cell types within a tissue, we here present a model-based probabilistic method that uses single cell data to deconvolve the cell mixtures in spatial data. To illustrate the capacity of our method, we use data from different experimental platforms and spatially map cell types from the mouse brain and developmental heart, which arrange as expected.

          Abstract

          Alma Andersson et al. present a probabilistic framework that integrates single-cell and bulk spatial transcriptomics in order to spatially map cell types onto their respective tissues. They apply their method to the developing human heart and mouse brain to demonstrate the power of the technique.

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          Most cited references16

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          xCell: digitally portraying the tissue cellular heterogeneity landscape

          Tissues are complex milieus consisting of numerous cell types. Several recent methods have attempted to enumerate cell subsets from transcriptomes. However, the available methods have used limited sources for training and give only a partial portrayal of the full cellular landscape. Here we present xCell, a novel gene signature-based method, and use it to infer 64 immune and stromal cell types. We harmonized 1822 pure human cell type transcriptomes from various sources and employed a curve fitting approach for linear comparison of cell types and introduced a novel spillover compensation technique for separating them. Using extensive in silico analyses and comparison to cytometry immunophenotyping, we show that xCell outperforms other methods. xCell is available at http://xCell.ucsf.edu/. Electronic supplementary material The online version of this article (doi:10.1186/s13059-017-1349-1) contains supplementary material, which is available to authorized users.
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            Visualization and analysis of gene expression in tissue sections by spatial transcriptomics.

            Analysis of the pattern of proteins or messengerRNAs (mRNAs) in histological tissue sections is a cornerstone in biomedical research and diagnostics. This typically involves the visualization of a few proteins or expressed genes at a time. We have devised a strategy, which we call "spatial transcriptomics," that allows visualization and quantitative analysis of the transcriptome with spatial resolution in individual tissue sections. By positioning histological sections on arrayed reverse transcription primers with unique positional barcodes, we demonstrate high-quality RNA-sequencing data with maintained two-dimensional positional information from the mouse brain and human breast cancer. Spatial transcriptomics provides quantitative gene expression data and visualization of the distribution of mRNAs within tissue sections and enables novel types of bioinformatics analyses, valuable in research and diagnostics.
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              Genome-wide atlas of gene expression in the adult mouse brain.

              Molecular approaches to understanding the functional circuitry of the nervous system promise new insights into the relationship between genes, brain and behaviour. The cellular diversity of the brain necessitates a cellular resolution approach towards understanding the functional genomics of the nervous system. We describe here an anatomically comprehensive digital atlas containing the expression patterns of approximately 20,000 genes in the adult mouse brain. Data were generated using automated high-throughput procedures for in situ hybridization and data acquisition, and are publicly accessible online. Newly developed image-based informatics tools allow global genome-scale structural analysis and cross-correlation, as well as identification of regionally enriched genes. Unbiased fine-resolution analysis has identified highly specific cellular markers as well as extensive evidence of cellular heterogeneity not evident in classical neuroanatomical atlases. This highly standardized atlas provides an open, primary data resource for a wide variety of further studies concerning brain organization and function.
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                Author and article information

                Contributors
                alma.andersson@scilifelab.se
                joakim.lundeberg@scilifelab.se
                Journal
                Commun Biol
                Commun Biol
                Communications Biology
                Nature Publishing Group UK (London )
                2399-3642
                9 October 2020
                9 October 2020
                2020
                : 3
                : 565
                Affiliations
                GRID grid.5037.1, ISNI 0000000121581746, Science for Life Laboratory, Department of Gene Technology, , KTH Royal Institute of Technology, ; Stockholm, Sweden
                Author information
                http://orcid.org/0000-0001-5941-7220
                http://orcid.org/0000-0002-5108-4481
                http://orcid.org/0000-0002-4035-5258
                http://orcid.org/0000-0003-4313-1601
                Article
                1247
                10.1038/s42003-020-01247-y
                7547664
                33037292
                bd815c7d-739f-430d-b1d2-4f14e4cae981
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 15 March 2020
                : 4 August 2020
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100004063, Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation);
                Funded by: FundRef https://doi.org/10.13039/100007436, Familjen Erling-Perssons Stiftelse (Erling-Persson Family Foundation);
                Funded by: FundRef https://doi.org/10.13039/501100001729, Stiftelsen för Strategisk Forskning (Swedish Foundation for Strategic Research);
                Funded by: Olav Thon Stiftelsen, Postboks 489 Sentrum, 0105 Oslo
                Categories
                Article
                Custom metadata
                © The Author(s) 2020

                data integration,computational models,transcriptomics

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