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From pathway to population--a multiscale model of juxtacrine EGFR-MAPK signalling.

Walker DC, Georgopoulos NT, Southgate J - BMC Syst Biol (2008)

Bottom Line: A model consisting of a single pair of interacting agents predicted very different Erk activation (phosphorylation) profiles, depending on the formation rate and stability of intercellular contacts, with the slow formation of stable contacts resulting in low but sustained activation of Erk, and transient contacts resulting in a transient Erk signal.These results illustrate that mean experimental data obtained from analysing entire cell populations is an oversimplification, and should not be extrapolated to deduce the signal:response paradigm of individual cells.This multi-scale, multi-paradigm approach to biological simulation provides an important conceptual tool in addressing how information may be integrated over multiple scales to predict the behaviour of a biological system.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Computer Science, University of Sheffield, Kroto Research Institute, North Campus, Broad Lane, Sheffield, S3 7HQ, UK. d.c.walker@sheffield.ac.uk

ABSTRACT

Background: Most mathematical models of biochemical pathways consider either signalling events that take place within a single cell in isolation, or an 'average' cell which is considered to be representative of a cell population. Likewise, experimental measurements are often averaged over populations consisting of hundreds of thousands of cells. This approach ignores the fact that even within a genetically-homogeneous population, local conditions may influence cell signalling and result in phenotypic heterogeneity. We have developed a multi-scale computational model that accounts for emergent heterogeneity arising from the influences of intercellular signalling on individual cells within a population. Our approach was to develop an ODE model of juxtacrine EGFR-ligand activation of the MAPK intracellular pathway and to couple this to an agent-based representation of individual cells in an expanding epithelial cell culture population. This multi-scale, multi-paradigm approach has enabled us to simulate Extracellular signal-regulated kinase (Erk) activation in a population of cells and to examine the consequences of interpretation at a single cell or population-based level using virtual assays.

Results: A model consisting of a single pair of interacting agents predicted very different Erk activation (phosphorylation) profiles, depending on the formation rate and stability of intercellular contacts, with the slow formation of stable contacts resulting in low but sustained activation of Erk, and transient contacts resulting in a transient Erk signal. Extension of this model to a population consisting of hundreds to thousands of interacting virtual cells revealed that the activated Erk profile measured across the entire cell population was very different and may appear to contradict individual cell findings, reflecting heterogeneity in population density across the culture. This prediction was supported by immunolabelling of an epithelial cell population grown in vitro, which confirmed heterogeneity of Erk activation.

Conclusion: These results illustrate that mean experimental data obtained from analysing entire cell populations is an oversimplification, and should not be extrapolated to deduce the signal:response paradigm of individual cells. This multi-scale, multi-paradigm approach to biological simulation provides an important conceptual tool in addressing how information may be integrated over multiple scales to predict the behaviour of a biological system.

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Erk-PP immunofluoresence results. Distribution of fluorescently tagged Erk-PP in normal human urothelial cells maintained in low 0.09 mM (a) and physiological 2.0 mM (b) calcium. c) and d) show position of nuclei.
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Figure 6: Erk-PP immunofluoresence results. Distribution of fluorescently tagged Erk-PP in normal human urothelial cells maintained in low 0.09 mM (a) and physiological 2.0 mM (b) calcium. c) and d) show position of nuclei.

Mentions: Testing the agent-only model with the rule sets described in Methods was found to give an increased incidence of E-cadherin-mediated bonding in low calcium conditions than we have described in our previous modelling studies. Comparison of simulated E-cadherin-mediated contact incidence at different cell densities gave good qualitative agreement with the results of an E-cadherin immunofluorescence microscopy study carried out using cultured NHU cells maintained in growth media containing 0.09 mM and 2.0 mM (physiological) calcium concentrations, respectively, as shown in figure 6.


From pathway to population--a multiscale model of juxtacrine EGFR-MAPK signalling.

Walker DC, Georgopoulos NT, Southgate J - BMC Syst Biol (2008)

Erk-PP immunofluoresence results. Distribution of fluorescently tagged Erk-PP in normal human urothelial cells maintained in low 0.09 mM (a) and physiological 2.0 mM (b) calcium. c) and d) show position of nuclei.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2651861&req=5

Figure 6: Erk-PP immunofluoresence results. Distribution of fluorescently tagged Erk-PP in normal human urothelial cells maintained in low 0.09 mM (a) and physiological 2.0 mM (b) calcium. c) and d) show position of nuclei.
Mentions: Testing the agent-only model with the rule sets described in Methods was found to give an increased incidence of E-cadherin-mediated bonding in low calcium conditions than we have described in our previous modelling studies. Comparison of simulated E-cadherin-mediated contact incidence at different cell densities gave good qualitative agreement with the results of an E-cadherin immunofluorescence microscopy study carried out using cultured NHU cells maintained in growth media containing 0.09 mM and 2.0 mM (physiological) calcium concentrations, respectively, as shown in figure 6.

Bottom Line: A model consisting of a single pair of interacting agents predicted very different Erk activation (phosphorylation) profiles, depending on the formation rate and stability of intercellular contacts, with the slow formation of stable contacts resulting in low but sustained activation of Erk, and transient contacts resulting in a transient Erk signal.These results illustrate that mean experimental data obtained from analysing entire cell populations is an oversimplification, and should not be extrapolated to deduce the signal:response paradigm of individual cells.This multi-scale, multi-paradigm approach to biological simulation provides an important conceptual tool in addressing how information may be integrated over multiple scales to predict the behaviour of a biological system.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Computer Science, University of Sheffield, Kroto Research Institute, North Campus, Broad Lane, Sheffield, S3 7HQ, UK. d.c.walker@sheffield.ac.uk

ABSTRACT

Background: Most mathematical models of biochemical pathways consider either signalling events that take place within a single cell in isolation, or an 'average' cell which is considered to be representative of a cell population. Likewise, experimental measurements are often averaged over populations consisting of hundreds of thousands of cells. This approach ignores the fact that even within a genetically-homogeneous population, local conditions may influence cell signalling and result in phenotypic heterogeneity. We have developed a multi-scale computational model that accounts for emergent heterogeneity arising from the influences of intercellular signalling on individual cells within a population. Our approach was to develop an ODE model of juxtacrine EGFR-ligand activation of the MAPK intracellular pathway and to couple this to an agent-based representation of individual cells in an expanding epithelial cell culture population. This multi-scale, multi-paradigm approach has enabled us to simulate Extracellular signal-regulated kinase (Erk) activation in a population of cells and to examine the consequences of interpretation at a single cell or population-based level using virtual assays.

Results: A model consisting of a single pair of interacting agents predicted very different Erk activation (phosphorylation) profiles, depending on the formation rate and stability of intercellular contacts, with the slow formation of stable contacts resulting in low but sustained activation of Erk, and transient contacts resulting in a transient Erk signal. Extension of this model to a population consisting of hundreds to thousands of interacting virtual cells revealed that the activated Erk profile measured across the entire cell population was very different and may appear to contradict individual cell findings, reflecting heterogeneity in population density across the culture. This prediction was supported by immunolabelling of an epithelial cell population grown in vitro, which confirmed heterogeneity of Erk activation.

Conclusion: These results illustrate that mean experimental data obtained from analysing entire cell populations is an oversimplification, and should not be extrapolated to deduce the signal:response paradigm of individual cells. This multi-scale, multi-paradigm approach to biological simulation provides an important conceptual tool in addressing how information may be integrated over multiple scales to predict the behaviour of a biological system.

Show MeSH
Related in: MedlinePlus