Redefining Signaling Pathways with an Expanding Single-Cell Toolbox

Gaudet, Suzanne; Miller‐Jensen, Kathryn

doi:10.1016/j.tibtech.2016.02.009

Cited by 43 publications

(27 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent technological advances in single-cell analysis makes it possible to address some of these issues and understand how variability in cytokine-induced signals leads to different cell fates. These include advances in single-cell analysis, imaging, and ‘omics’ techniques [35,79–81]. …”

Section: Single-cell Analysismentioning

confidence: 99%

Demystifying the cytokine network: Mathematical models point the way

2017

View full text Add to dashboard Cite

Cytokines provide the means by which immune cells communicate with each other and with parenchymal cells. There are over one hundred cytokines and many exist in families that share receptor components and signal transduction pathways, creating complex networks. Reductionist approaches to understanding the role of specific cytokines, through the use of gene-targeted mice, have revealed further complexity in the form of redundancy and pleiotropy in cytokine function. Creating an understanding of the complex interactions between cytokines and their target cells is challenging experimentally. Mathematical and computational modeling provides a robust set of tools by which complex interactions between cytokines can be studied and analyzed, in the process creating novel insights that can be further tested experimentally. This review will discuss and provide examples of the different modeling approaches that have been used to increase our understanding of cytokine networks. This includes discussion of knowledge-based and data-driven modeling approaches and the recent advance in single-cell analysis. The use of modeling to optimize cytokine-based therapies will also be discussed.

show abstract

Section: Single-cell Analysismentioning

confidence: 99%

Demystifying the cytokine network: Mathematical models point the way

2017

View full text Add to dashboard Cite

show abstract

“…More recently, myriad single-cell measures have been used in combination to elucidate viral and cellular mechanisms [2,7,17–25]. Many of these studies have been aided by the development of live-cell imaging of fluorescent reporters.…”

Section: Introductionmentioning

confidence: 99%

Quantitative profiling of innate immune activation by viral infection in single cells

2017

View full text Add to dashboard Cite

Cells infected by viruses can exhibit diverse patterns of viral and cellular gene expression. The patterns arise in part from the stochastic or noisy reaction kinetics associated with the small number of genomes, enzymes, and other molecules that typically initiate virus replication and activate cellular anti-viral defenses. It is not known what features, if any, of the early viral or cellular gene expression correlate with later processes of viral replication or cell survival. Here we used two fluorescent reporters to visualize innate immune activation of human prostate cancer (PC3) cells against infection by vesicular stomatitis virus. The cells were engineered to express green-fluorescent protein under control of the promoter for IFIT2, an interferon-sensitive component of the anti-viral response, while red-fluorescent protein was expressed as a byproduct of virus infection. To isolate and quantitatively analyze single-cells, we used a unique microwell array device and open-source image processing software. Kinetic analysis of viral and cellular reporter profiles from hundreds of cells revealed novel relationships between gene expression and the outcome of infection. Specifically, the relative timing rather than the magnitude of the viral gene expression and innate immune activation correlated with the infection outcome. Earlier viral or anti-viral gene expression favored or hindered virus growth, respectively. Further, analysis of kinetic parameters estimated from these data suggests a trade-off between robust antiviral signaling and cell death, as indicated by a higher rate of detectable cell lysis in infected cells with a detectable immune response. In short, cells that activate an immune response lyse at a higher rate. More broadly, we demonstrate how the intrinsic heterogeneity of individual cell behaviors can be exploited to discover features of viral and host gene expression that correlate with single-cell outcomes, which will ultimately impact whether or not infections spread.

show abstract

“…In recent years, the investigation of non-genetic cell-to-cell variability has been propelled by the development of sophisticated tools to analyze individual living cells [20, 21]. Single cell methods deliver invaluable insights into mechanisms of regulation and function that are concealed in bulk, population-level studies measuring ensemble-averaged cellular responses [22–25].…”

Section: Introductionmentioning

confidence: 99%

Determining the Limitations and Benefits of Noise in Gene Regulation and Signal Transduction through Single Cell, Microscopy-Based Analysis

Harton

Batchelor

2017

Journal of Molecular Biology

View full text Add to dashboard Cite

Stochastic fluctuations, termed “noise,” in the level of biological molecules can greatly impact cellular functions. While biological noise can sometimes be detrimental, recent studies have provided an increasing number of examples in which biological noise can be functionally beneficial. Rather than provide an exhaustive review of the growing literature in this field, in this review we focus on single cell studies based on quantitative microscopy that have generated a deeper understanding of the sources, characteristics, limitations, and benefits of biological noise. Specifically, we highlight studies showing how noise can help coordinate the expression of multiple downstream target genes, impact the channel capacity of signaling networks, and interact synergistically with oscillatory dynamics to enhance the sensitivity of signal processing. We conclude with a discussion of current challenges and future opportunities.

show abstract

Redefining Signaling Pathways with an Expanding Single-Cell Toolbox

Cited by 43 publications

References 71 publications

Demystifying the cytokine network: Mathematical models point the way

Demystifying the cytokine network: Mathematical models point the way

Quantitative profiling of innate immune activation by viral infection in single cells

Determining the Limitations and Benefits of Noise in Gene Regulation and Signal Transduction through Single Cell, Microscopy-Based Analysis

Contact Info

Product

Resources

About