A Cyclin Distributed Cell Cycle Model in GS-NS0
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Mammalian cell factories are typically complex production systems as productivity and product quality are controlled by a large number of coordinated metabolic reactions influenced by culture parameters. The cell cycle is at the centre of cellular growth, death, and productivity, which varies during the different cell cycle phases. In order to rigorously capture the cell cycle heterogeneity, utilization of biomarkers is required. Herein, we present, for the first time, a biologically accurate and experimentally supported cell cycle model for the GS-NS0 cell line. In order to develop the model, the cell line's cell cycle blueprint was elucidated by studying the timing of expression of two cyclins (E and B) and cell cycle proliferation times by flow cytometry. The formulated model is hybrid consisting both on unstructured and structured elements. The cell cycle is segregated/structured by using a multistaged (G1/G0, S, G2/M) and multivariable (cyclin E, DNA and cyclin B) PBE, and it is coupled to an unstructured metabolic model. A model approximation and discretization solution is implemented making it unconditionally stable, fully conservative and computationally tractable (solution time ~ 4 s). 2014 Elsevier B.V.