Abstract
BackgroundThe 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 FindingsWe 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.ConclusionsThe 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.
Highlights
Phenotypic heterogeneity in genetically homogenous cell populations is frequently observed in in vitro cell cultures
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
The basic model presented in this paper simulates the growth of a clonal cell population and provides a simple framework for testing the ‘‘intrinsic’’ and ‘‘extrinsic’’ hypotheses on the origin of phenotypic heterogeneity
Summary
Phenotypic heterogeneity in genetically homogenous cell populations is frequently observed in in vitro cell cultures. Phenotypic heterogeneity is systematically observed in cultures of various lines of genetically identical cells even in controlled environments. These different phenotypes can be strikingly different; for example, non malignant cells can spontaneously produce neoplastic subclones at a frequency dependent on the culture conditions. 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 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. The ‘‘intrinsic’’ model shows some other aspects of reality: The phenotypic switch is not triggered exclusively by the local environmental variations, and depends to some extent on the phenotypic intrinsic robustness of the cells
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