Single-cell RNA-seq reveals dynamic paracrine control of cellular variation

Alex K. Shalek, Rahul Satija (), Joe Shuga, John J. Trombetta, Dave Gennert, Diana Lu, Peilin Chen, Rona S. Gertner, Jellert T. Gaublomme, Nir Yosef, Schraga Schwartz, Brian Fowler, Suzanne Weaver, Jing Wang, Xiaohui Wang, Ruihua Ding, Raktima Raychowdhury, Nir Friedman, Nir Hacohen, Hongkun Park (), Andrew P. May () and Aviv Regev
Additional contact information
Alex K. Shalek: Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA
Rahul Satija: Broad Institute of MIT and Harvard, 7 Cambridge Center
Joe Shuga: Fluidigm Corporation, 7000 Shoreline Court, Suite 100, South San Francisco, California 94080, USA
John J. Trombetta: Broad Institute of MIT and Harvard, 7 Cambridge Center
Dave Gennert: Broad Institute of MIT and Harvard, 7 Cambridge Center
Diana Lu: Broad Institute of MIT and Harvard, 7 Cambridge Center
Peilin Chen: Fluidigm Corporation, 7000 Shoreline Court, Suite 100, South San Francisco, California 94080, USA
Rona S. Gertner: Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA
Jellert T. Gaublomme: Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA
Nir Yosef: Broad Institute of MIT and Harvard, 7 Cambridge Center
Schraga Schwartz: Broad Institute of MIT and Harvard, 7 Cambridge Center
Brian Fowler: Fluidigm Corporation, 7000 Shoreline Court, Suite 100, South San Francisco, California 94080, USA
Suzanne Weaver: Fluidigm Corporation, 7000 Shoreline Court, Suite 100, South San Francisco, California 94080, USA
Jing Wang: Fluidigm Corporation, 7000 Shoreline Court, Suite 100, South San Francisco, California 94080, USA
Xiaohui Wang: Fluidigm Corporation, 7000 Shoreline Court, Suite 100, South San Francisco, California 94080, USA
Ruihua Ding: Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA
Raktima Raychowdhury: Broad Institute of MIT and Harvard, 7 Cambridge Center
Nir Friedman: School of Computer Science and Engineering, Hebrew University, 91904 Jerusalem, Israel
Nir Hacohen: Broad Institute of MIT and Harvard, 7 Cambridge Center
Hongkun Park: Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA
Andrew P. May: Fluidigm Corporation, 7000 Shoreline Court, Suite 100, South San Francisco, California 94080, USA
Aviv Regev: Broad Institute of MIT and Harvard, 7 Cambridge Center

Nature, 2014, vol. 510, issue 7505, 363-369

Abstract: Abstract High-throughput single-cell transcriptomics offers an unbiased approach for understanding the extent, basis and function of gene expression variation between seemingly identical cells. Here we sequence single-cell RNA-seq libraries prepared from over 1,700 primary mouse bone-marrow-derived dendritic cells spanning several experimental conditions. We find substantial variation between identically stimulated dendritic cells, in both the fraction of cells detectably expressing a given messenger RNA and the transcript’s level within expressing cells. Distinct gene modules are characterized by different temporal heterogeneity profiles. In particular, a ‘core’ module of antiviral genes is expressed very early by a few ‘precocious’ cells in response to uniform stimulation with a pathogenic component, but is later activated in all cells. By stimulating cells individually in sealed microfluidic chambers, analysing dendritic cells from knockout mice, and modulating secretion and extracellular signalling, we show that this response is coordinated by interferon-mediated paracrine signalling from these precocious cells. Notably, preventing cell-to-cell communication also substantially reduces variability between cells in the expression of an early-induced ‘peaked’ inflammatory module, suggesting that paracrine signalling additionally represses part of the inflammatory program. Our study highlights the importance of cell-to-cell communication in controlling cellular heterogeneity and reveals general strategies that multicellular populations can use to establish complex dynamic responses.

Date: 2014
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DOI: 10.1038/nature13437

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