Dissecting cellular crosstalk by sequencing physically interacting cells

• Published in: Nature biotechnology Vol. 38; no. 5; pp. 629 - 637
• Main Authors: Giladi, Amir, Cohen, Merav, Medaglia, Chiara, Baran, Yael, Li, Baoguo, Zada, Mor, Bost, Pierre, Blecher-Gonen, Ronnie, Salame, Tomer-Meir, Mayer, Johannes U., David, Eyal, Ronchese, Franca, Tanay, Amos, Amit, Ido
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2020; Nature Publishing Group
• Subjects: 631/250/516; 631/337/2019; 631/61/191/2018; 631/61/212/2019; Agriculture; Algorithms; Analysis; Animals; Animals, Newborn; Bioinformatics; Biological activity; Biomedical and Life Sciences; Biomedical Engineering/Biotechnology; Biomedicine; Biotechnology; Cell Communication; Cell differentiation; Cell interactions; Cell migration; Cell proliferation; Cells, Cultured; Computational Biology; Computer applications; Crosstalk; Dendritic cells; Dendritic Cells - chemistry; Dendritic Cells - cytology; Female; Flow Cytometry; Gene Expression Profiling - methods; Gene mapping; Gene sequencing; Genomics; Immunoregulation; Life Sciences; Lung - chemistry; Lung - cytology; Lymph nodes; Lymphocytes; Lymphocytes T; Mice; Neonates; Ribonucleic acid; RNA; Sequence Analysis, RNA; Single-Cell Analysis - methods; T cells; T-Lymphocytes - chemistry; T-Lymphocytes - cytology; Canada
• ISSN: 1087-0156; 1546-1696
• DOI: 10.1038/s41587-020-0442-2

Crosstalk between neighboring cells underlies many biological processes, including cell signaling, proliferation and differentiation. Current single-cell genomic technologies profile each cell separately after tissue dissociation, losing information on cell–cell interactions. In the present study, we present an approach for sequencing physically interacting cells (PIC-seq), which combines cell sorting of physically interacting cells (PICs) with single-cell RNA-sequencing. Using computational modeling, PIC-seq systematically maps in situ cellular interactions and characterizes their molecular crosstalk. We apply PIC-seq to interrogate diverse interactions including immune–epithelial PICs in neonatal murine lungs. Focusing on interactions between T cells and dendritic cells (DCs) in vitro and in vivo, we map T cell–DC interaction preferences, and discover regulatory T cells as a major T cell subtype interacting with DCs in mouse draining lymph nodes. Analysis of T cell–DC pairs reveals an interaction-specific program between pathogen-presenting migratory DCs and T cells. PIC-seq provides a direct and broadly applicable technology to characterize intercellular interaction-specific pathways at high resolution. PIC-seq characterizes cellular crosstalk by sorting and sequencing physically interacting cells.