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The origin of phenotypic heterogeneity in a clonal cell population in vitro.

Stockholm D, Benchaouir R, Picot J, Rameau P, Neildez TM, Landini G, Laplace-Builhé C, Paldi A - PLoS ONE (2007)

Bottom Line: The key predictions of the two models were confronted with the results obtained experimentally using a myogenic cell line.The observations emphasize the importance of the "ecological" context and suggest that, consistently with the "extrinsic" model, local stochastic interactions between phenotypically identical cells play a key role in the initiation of phenotypic switch.Nevertheless, the "intrinsic" model also shows some other aspects of reality: The phenotypic switch is not triggered exclusively by the local environmental variations, but also depends to some extent on the phenotypic intrinsic robustness of the cells.

View Article: PubMed Central - PubMed

Affiliation: GENETHON-Centre National de la Recherche Scientifique (CNRS), UMR 8115, Evry, France.

ABSTRACT

Background: The spontaneous emergence of phenotypic heterogeneity in clonal populations of mammalian cells in vitro is a rule rather than an exception. We consider two simple, mutually non-exclusive models that explain the generation of diverse cell types in a homogeneous population. In the first model, the phenotypic switch is the consequence of extrinsic factors. Initially identical cells may become different because they encounter different local environments that induce adaptive responses. According to the second model, the phenotypic switch is intrinsic to the cells that may occur even in homogeneous environments.

Principal findings: We have investigated the "extrinsic" and the "intrinsic" mechanisms using computer simulations and experimentation. First, we simulated in silico the emergence of two cell types in a clonal cell population using a multiagent model. Both mechanisms produced stable phenotypic heterogeneity, but the distribution of the cell types was different. The "intrinsic" model predicted an even distribution of the rare phenotype cells, while in the "extrinsic" model these cells formed small clusters. The key predictions of the two models were confronted with the results obtained experimentally using a myogenic cell line.

Conclusions: The observations emphasize the importance of the "ecological" context and suggest that, consistently with the "extrinsic" model, local stochastic interactions between phenotypically identical cells play a key role in the initiation of phenotypic switch. Nevertheless, the "intrinsic" model also shows some other aspects of reality: The phenotypic switch is not triggered exclusively by the local environmental variations, but also depends to some extent on the phenotypic intrinsic robustness of the cells.

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The “extrinsic” model.A: Simulations with the “extrinsic” model using increasing values of Nex. Note the increasing proportion and clustering of type A (red) cells with increasing Nex. In all simulations Nmax death = 40 was used. B: Analysis of type A cell distribution as a function of average migration velocity and varying Nex using the standardized nearest neighbour distance. Type A cells were clustered (w<1) at all but small average velocity values at all Nex values analysed.
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pone-0000394-g004: The “extrinsic” model.A: Simulations with the “extrinsic” model using increasing values of Nex. Note the increasing proportion and clustering of type A (red) cells with increasing Nex. In all simulations Nmax death = 40 was used. B: Analysis of type A cell distribution as a function of average migration velocity and varying Nex using the standardized nearest neighbour distance. Type A cells were clustered (w<1) at all but small average velocity values at all Nex values analysed.

Mentions: A typical simulation starts with a single A cell, with type B cells appearing first at the centre of the growing population (where the cell density is the highest). Local fluctuations in cell density due to random cell movement and cell death sometimes allow B cells to switch back to type A. During the growth phase, A cells are observed on the periphery of the population (Fig. 3A) but when the cells fill all the available space, the subpopulations reach a dynamic equilibrium with [A]/[B] determined by the Nex/R ratio (see Fig. 4 A). When A cells switch to B type at low density (during the equilibrium phase) the majority of the population is composed of B cells. However, if Nex is close to Nmax death, the number of A and B cells is nearly equal. When compared to the “intrinsic” model, the spatial distribution of the cells in this “extrinsic” model is markedly different. The rare phenotype A cells typically form groups or clusters in areas with low local cell density for all tested values of Nex. The B cells are distributed randomly when Nex<Nmax death, but some clustering appears when Nex approaches Nmax death and the sizes of the two subpopulations become comparable (not shown). We also examined the effect of migration velocity on the spatial distribution of cells and found that clustering of A cells was not affected by this parameter (Fig. 4B). Therefore, cluster formation seems to be a generic feature of the “extrinsic” model and robust in the range of the parameters considered.


The origin of phenotypic heterogeneity in a clonal cell population in vitro.

Stockholm D, Benchaouir R, Picot J, Rameau P, Neildez TM, Landini G, Laplace-Builhé C, Paldi A - PLoS ONE (2007)

The “extrinsic” model.A: Simulations with the “extrinsic” model using increasing values of Nex. Note the increasing proportion and clustering of type A (red) cells with increasing Nex. In all simulations Nmax death = 40 was used. B: Analysis of type A cell distribution as a function of average migration velocity and varying Nex using the standardized nearest neighbour distance. Type A cells were clustered (w<1) at all but small average velocity values at all Nex values analysed.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC1851097&req=5

pone-0000394-g004: The “extrinsic” model.A: Simulations with the “extrinsic” model using increasing values of Nex. Note the increasing proportion and clustering of type A (red) cells with increasing Nex. In all simulations Nmax death = 40 was used. B: Analysis of type A cell distribution as a function of average migration velocity and varying Nex using the standardized nearest neighbour distance. Type A cells were clustered (w<1) at all but small average velocity values at all Nex values analysed.
Mentions: A typical simulation starts with a single A cell, with type B cells appearing first at the centre of the growing population (where the cell density is the highest). Local fluctuations in cell density due to random cell movement and cell death sometimes allow B cells to switch back to type A. During the growth phase, A cells are observed on the periphery of the population (Fig. 3A) but when the cells fill all the available space, the subpopulations reach a dynamic equilibrium with [A]/[B] determined by the Nex/R ratio (see Fig. 4 A). When A cells switch to B type at low density (during the equilibrium phase) the majority of the population is composed of B cells. However, if Nex is close to Nmax death, the number of A and B cells is nearly equal. When compared to the “intrinsic” model, the spatial distribution of the cells in this “extrinsic” model is markedly different. The rare phenotype A cells typically form groups or clusters in areas with low local cell density for all tested values of Nex. The B cells are distributed randomly when Nex<Nmax death, but some clustering appears when Nex approaches Nmax death and the sizes of the two subpopulations become comparable (not shown). We also examined the effect of migration velocity on the spatial distribution of cells and found that clustering of A cells was not affected by this parameter (Fig. 4B). Therefore, cluster formation seems to be a generic feature of the “extrinsic” model and robust in the range of the parameters considered.

Bottom Line: The key predictions of the two models were confronted with the results obtained experimentally using a myogenic cell line.The observations emphasize the importance of the "ecological" context and suggest that, consistently with the "extrinsic" model, local stochastic interactions between phenotypically identical cells play a key role in the initiation of phenotypic switch.Nevertheless, the "intrinsic" model also shows some other aspects of reality: The phenotypic switch is not triggered exclusively by the local environmental variations, but also depends to some extent on the phenotypic intrinsic robustness of the cells.

View Article: PubMed Central - PubMed

Affiliation: GENETHON-Centre National de la Recherche Scientifique (CNRS), UMR 8115, Evry, France.

ABSTRACT

Background: The spontaneous emergence of phenotypic heterogeneity in clonal populations of mammalian cells in vitro is a rule rather than an exception. We consider two simple, mutually non-exclusive models that explain the generation of diverse cell types in a homogeneous population. In the first model, the phenotypic switch is the consequence of extrinsic factors. Initially identical cells may become different because they encounter different local environments that induce adaptive responses. According to the second model, the phenotypic switch is intrinsic to the cells that may occur even in homogeneous environments.

Principal findings: We have investigated the "extrinsic" and the "intrinsic" mechanisms using computer simulations and experimentation. First, we simulated in silico the emergence of two cell types in a clonal cell population using a multiagent model. Both mechanisms produced stable phenotypic heterogeneity, but the distribution of the cell types was different. The "intrinsic" model predicted an even distribution of the rare phenotype cells, while in the "extrinsic" model these cells formed small clusters. The key predictions of the two models were confronted with the results obtained experimentally using a myogenic cell line.

Conclusions: The observations emphasize the importance of the "ecological" context and suggest that, consistently with the "extrinsic" model, local stochastic interactions between phenotypically identical cells play a key role in the initiation of phenotypic switch. Nevertheless, the "intrinsic" model also shows some other aspects of reality: The phenotypic switch is not triggered exclusively by the local environmental variations, but also depends to some extent on the phenotypic intrinsic robustness of the cells.

Show MeSH