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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 basic parameters in the model.A: Multiagent computer simulation of the “extrinsic” and “intrinsic” mechanisms. Cells migrate and divide in the same way in the two models, and cell death is a function of the local cell density. The phenotypic switch of each cell is either dependent on the local cell density in the “extrinsic” (left) or a fixed probability in the “intrinsic” (right) model.” N” is the number of neighbours in the circle with a radius “R”; “pd” is the probability of division; p1 and p2 are the probabilities of the A and B type cells to change their phenotype in the “intrinsic” model; Nex is the threshold, given by the number of neighbours. B: Characteristics of the cell migration in the computer model and in vitro, as observed in the cultures of the C2C12 cell line. The trajectories of a single cell simulated in silico (left) and its in vitro counterpart (right, determined by video microscopy), are shown. C: The exponential distribution of the cumulative velocity magnitudes in the simulation (left) and in vitro, as determined experimentally (right).
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pone-0000394-g001: The basic parameters in the model.A: Multiagent computer simulation of the “extrinsic” and “intrinsic” mechanisms. Cells migrate and divide in the same way in the two models, and cell death is a function of the local cell density. The phenotypic switch of each cell is either dependent on the local cell density in the “extrinsic” (left) or a fixed probability in the “intrinsic” (right) model.” N” is the number of neighbours in the circle with a radius “R”; “pd” is the probability of division; p1 and p2 are the probabilities of the A and B type cells to change their phenotype in the “intrinsic” model; Nex is the threshold, given by the number of neighbours. B: Characteristics of the cell migration in the computer model and in vitro, as observed in the cultures of the C2C12 cell line. The trajectories of a single cell simulated in silico (left) and its in vitro counterpart (right, determined by video microscopy), are shown. C: The exponential distribution of the cumulative velocity magnitudes in the simulation (left) and in vitro, as determined experimentally (right).

Mentions: Since cell migration plays a crucial role in the model, the migration characteristics were defined on the basis of videomicroscopic observations of growing C2C12 cell cultures (more than 3000 cell velocity values over an 18h period). In accordance with earlier reports [11], [12] we found that cells migrate randomly (Fig. 1B) and that the cumulative velocity magnitudes (at a given time) as well as the velocities of the same cell over long periods, follow an exponential distribution (Fig. 1C). Therefore, the migration velocities of the simulated cells were generated using an exponential probability distribution function.


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 basic parameters in the model.A: Multiagent computer simulation of the “extrinsic” and “intrinsic” mechanisms. Cells migrate and divide in the same way in the two models, and cell death is a function of the local cell density. The phenotypic switch of each cell is either dependent on the local cell density in the “extrinsic” (left) or a fixed probability in the “intrinsic” (right) model.” N” is the number of neighbours in the circle with a radius “R”; “pd” is the probability of division; p1 and p2 are the probabilities of the A and B type cells to change their phenotype in the “intrinsic” model; Nex is the threshold, given by the number of neighbours. B: Characteristics of the cell migration in the computer model and in vitro, as observed in the cultures of the C2C12 cell line. The trajectories of a single cell simulated in silico (left) and its in vitro counterpart (right, determined by video microscopy), are shown. C: The exponential distribution of the cumulative velocity magnitudes in the simulation (left) and in vitro, as determined experimentally (right).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC1851097&req=5

pone-0000394-g001: The basic parameters in the model.A: Multiagent computer simulation of the “extrinsic” and “intrinsic” mechanisms. Cells migrate and divide in the same way in the two models, and cell death is a function of the local cell density. The phenotypic switch of each cell is either dependent on the local cell density in the “extrinsic” (left) or a fixed probability in the “intrinsic” (right) model.” N” is the number of neighbours in the circle with a radius “R”; “pd” is the probability of division; p1 and p2 are the probabilities of the A and B type cells to change their phenotype in the “intrinsic” model; Nex is the threshold, given by the number of neighbours. B: Characteristics of the cell migration in the computer model and in vitro, as observed in the cultures of the C2C12 cell line. The trajectories of a single cell simulated in silico (left) and its in vitro counterpart (right, determined by video microscopy), are shown. C: The exponential distribution of the cumulative velocity magnitudes in the simulation (left) and in vitro, as determined experimentally (right).
Mentions: Since cell migration plays a crucial role in the model, the migration characteristics were defined on the basis of videomicroscopic observations of growing C2C12 cell cultures (more than 3000 cell velocity values over an 18h period). In accordance with earlier reports [11], [12] we found that cells migrate randomly (Fig. 1B) and that the cumulative velocity magnitudes (at a given time) as well as the velocities of the same cell over long periods, follow an exponential distribution (Fig. 1C). Therefore, the migration velocities of the simulated cells were generated using an exponential probability distribution function.

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