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Novel column generation-based optimization approach for poly-pathway kinetic model applied to CHO cell culture
- Hagrot, Erika, Oddsdóttir, Hildur Æsa, Mäkinen, Meeri, Forsgren, Anders, Chotteau, Véronique
- Metabolic Engineering Communications 2019 v.8 pp. e00083
- Chinese hamsters, algorithms, amino acids, animal ovaries, biochemical pathways, bioprocessing, cell culture, kinetics, mathematical models, metabolism, metabolites, prediction, secretion
- Mathematical modelling can provide precious tools for bioprocess simulation, prediction, control and optimization of mammalian cell-based cultures. In this paper we present a novel method to generate kinetic models of such cultures, rendering complex metabolic networks in a poly-pathway kinetic model. The model is based on subsets of elementary flux modes (EFMs) to generate macro-reactions. Thanks to our column generation-based optimization algorithm, the experimental data are used to identify the EFMs, which are relevant to the data. Here the systematic enumeration of all the EFMs is eliminated and a network including a large number of reactions can be considered. In particular, the poly-pathway model can simulate multiple metabolic behaviors in response to changes in the culture conditions.We apply the method to a network of 126 metabolic reactions describing cultures of antibody-producing Chinese hamster ovary cells, and generate a poly-pathway model that simulates multiple experimental conditions obtained in response to variations in amino acid availability. A good fit between simulated and experimental data is obtained, rendering the variations in the growth, product, and metabolite uptake/secretion rates. The intracellular reaction fluxes simulated by the model are explored, linking variations in metabolic behavior to adaptations of the intracellular metabolism.