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A multi-scale approach reveals that NF-κB cRel enforces a B-cell decision to divide.

Shokhirev MN, Almaden J, Davis-Turak J, Birnbaum HA, Russell TM, Vargas JA, Hoffmann A - Mol. Syst. Biol. (2015)

Bottom Line: B-lymphocyte population dynamics, which are predictive of immune response and vaccine effectiveness, are determined by individual cells undergoing division or death seemingly stochastically.Combining modeling and experimentation, we found that NF-κB cRel enforces the execution of a cellular decision between mutually exclusive fates by promoting survival in growing cells.We show that a multi-scale modeling approach allows for the prediction of dynamic organ-level physiology in terms of intra-cellular molecular networks.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, Signaling Systems Laboratory, UCSD, La Jolla, CA, USA San Diego Center for Systems Biology, UCSD, La Jolla, CA, USA Bioinformatics and Systems Biology Graduate Program, UCSD, La Jolla, CA, USA.

No MeSH data available.


Developing a multi-scale understanding of the B-cell immune responseWe employed a multi-scale approach to studying the B-cell response. Time-lapse microscopy observations of B-cell populations revealed cellular growth trajectories, distribution of division and death time, as well as the fraction of cells responding in each generation. Single-cell molecular assays provided insights into the upregulation of key molecular players upon activation within individual cells. The number of cells in each generation was measured by the division tracking dye CFSE and deconvoluted into maximum-likelihood cellular parameters using the FlowMax computational tool. We used our observations to parameterize a multi-scale agent-based mathematical model consisting of established modules for signaling, apoptosis, and the cell cycle which allowed us to mechanistically study molecular perturbations on population dynamics.
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fig01: Developing a multi-scale understanding of the B-cell immune responseWe employed a multi-scale approach to studying the B-cell response. Time-lapse microscopy observations of B-cell populations revealed cellular growth trajectories, distribution of division and death time, as well as the fraction of cells responding in each generation. Single-cell molecular assays provided insights into the upregulation of key molecular players upon activation within individual cells. The number of cells in each generation was measured by the division tracking dye CFSE and deconvoluted into maximum-likelihood cellular parameters using the FlowMax computational tool. We used our observations to parameterize a multi-scale agent-based mathematical model consisting of established modules for signaling, apoptosis, and the cell cycle which allowed us to mechanistically study molecular perturbations on population dynamics.

Mentions: Here, we aimed to construct a multi-modular mathematical model that accounts for B-cell population dynamics in terms of intra-cellular molecular network dynamics. Starting at the B-cell population scale, we employed carboxyfluorescein succinimidyl ester (CFSE) flow cytometry and live time-lapse microscopy tracking of cell lineages to characterize the model topology and parameters at the cell biological scale. Starting at the molecular network scale, we used single-cell RNAseq and quantitative immunofluorescence to characterize the connections between several regulatory molecular network modules (Fig1).


A multi-scale approach reveals that NF-κB cRel enforces a B-cell decision to divide.

Shokhirev MN, Almaden J, Davis-Turak J, Birnbaum HA, Russell TM, Vargas JA, Hoffmann A - Mol. Syst. Biol. (2015)

Developing a multi-scale understanding of the B-cell immune responseWe employed a multi-scale approach to studying the B-cell response. Time-lapse microscopy observations of B-cell populations revealed cellular growth trajectories, distribution of division and death time, as well as the fraction of cells responding in each generation. Single-cell molecular assays provided insights into the upregulation of key molecular players upon activation within individual cells. The number of cells in each generation was measured by the division tracking dye CFSE and deconvoluted into maximum-likelihood cellular parameters using the FlowMax computational tool. We used our observations to parameterize a multi-scale agent-based mathematical model consisting of established modules for signaling, apoptosis, and the cell cycle which allowed us to mechanistically study molecular perturbations on population dynamics.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4358656&req=5

fig01: Developing a multi-scale understanding of the B-cell immune responseWe employed a multi-scale approach to studying the B-cell response. Time-lapse microscopy observations of B-cell populations revealed cellular growth trajectories, distribution of division and death time, as well as the fraction of cells responding in each generation. Single-cell molecular assays provided insights into the upregulation of key molecular players upon activation within individual cells. The number of cells in each generation was measured by the division tracking dye CFSE and deconvoluted into maximum-likelihood cellular parameters using the FlowMax computational tool. We used our observations to parameterize a multi-scale agent-based mathematical model consisting of established modules for signaling, apoptosis, and the cell cycle which allowed us to mechanistically study molecular perturbations on population dynamics.
Mentions: Here, we aimed to construct a multi-modular mathematical model that accounts for B-cell population dynamics in terms of intra-cellular molecular network dynamics. Starting at the B-cell population scale, we employed carboxyfluorescein succinimidyl ester (CFSE) flow cytometry and live time-lapse microscopy tracking of cell lineages to characterize the model topology and parameters at the cell biological scale. Starting at the molecular network scale, we used single-cell RNAseq and quantitative immunofluorescence to characterize the connections between several regulatory molecular network modules (Fig1).

Bottom Line: B-lymphocyte population dynamics, which are predictive of immune response and vaccine effectiveness, are determined by individual cells undergoing division or death seemingly stochastically.Combining modeling and experimentation, we found that NF-κB cRel enforces the execution of a cellular decision between mutually exclusive fates by promoting survival in growing cells.We show that a multi-scale modeling approach allows for the prediction of dynamic organ-level physiology in terms of intra-cellular molecular networks.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, Signaling Systems Laboratory, UCSD, La Jolla, CA, USA San Diego Center for Systems Biology, UCSD, La Jolla, CA, USA Bioinformatics and Systems Biology Graduate Program, UCSD, La Jolla, CA, USA.

No MeSH data available.