title: The origin of phenotypic heterogeneity in a clonal cell population in vitro.
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.
  
  
  RESULTS
  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.
authors: GENETHON-Centre National de la Recherche Scientifique (CNRS), UMR 8115, Evry, France.
authors: Daniel
authors: D
authors: Stockholm
authors: Rachid
authors: R
authors: Benchaouir
authors: Julien
authors: J
authors: Picot
authors: Philippe
authors: P
authors: Rameau
authors: Thi My Anh
authors: TM
authors: Neildez
authors: Gabriel
authors: G
authors: Landini
authors: Corinne
authors: C
authors: Laplace-Builhé
authors: Andras
authors: A
authors: Paldi
mesh_terms: D002999:Clone Cells; D006801:Humans; D066298:In Vitro Techniques; D008954:Models, Biological; D010641:Phenotype