Development of a mathematical model for evaluating the dynamics of normal and apoptotic Chinese hamster ovary cells

Naderi, Saeideh; Meshram, Mukesh; Wei, Catherine; McConkey, Brendan J.; Ingalls, Brian; Budman, Hector; Scharer, Jeno M.

doi:10.1002/btpr.647

Cited by 42 publications

(43 citation statements)

References 37 publications

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“…Specifically, the growth functions ( r i ) are glutamate-dependent (Equation 7). This dependency was introduced since it has been reported that glutamine, or glutamate in the GS system [50], is the main energy-yielding metabolic route [11, 51, 52] with over 90% flowing into the TCA cycle [53]. In addition, the cyclin growth functions ( r i = G1,G2 ) were also formulated as lactate-dependent since it has been reported [54, 55] that its concentration inhibits cell growth.…”

Section: Resultsmentioning

confidence: 99%

Cyclin and DNA Distributed Cell Cycle Model for GS-NS0 Cells

et al. 2015

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Mammalian cell cultures are intrinsically heterogeneous at different scales (molecular to bioreactor). The cell cycle is at the centre of capturing heterogeneity since it plays a critical role in the growth, death, and productivity of mammalian cell cultures. Current cell cycle models use biological variables (mass/volume/age) that are non-mechanistic, and difficult to experimentally determine, to describe cell cycle transition and capture culture heterogeneity. To address this problem, cyclins—key molecules that regulate cell cycle transition—have been utilized. Herein, a novel integrated experimental-modelling platform is presented whereby experimental quantification of key cell cycle metrics (cell cycle timings, cell cycle fractions, and cyclin expression determined by flow cytometry) is used to develop a cyclin and DNA distributed model for the industrially relevant cell line, GS-NS0. Cyclins/DNA synthesis rates were linked to stimulatory/inhibitory factors in the culture medium, which ultimately affect cell growth. Cell antibody productivity was characterized using cell cycle-specific production rates. The solution method delivered fast computational time that renders the model’s use suitable for model-based applications. Model structure was studied by global sensitivity analysis (GSA), which identified parameters with a significant effect on the model output, followed by re-estimation of its significant parameters from a control set of batch experiments. A good model fit to the experimental data, both at the cell cycle and viable cell density levels, was observed. The cell population heterogeneity of disturbed (after cell arrest) and undisturbed cell growth was captured proving the versatility of the modelling approach. Cell cycle models able to capture population heterogeneity facilitate in depth understanding of these complex systems and enable systematic formulation of culture strategies to improve growth and productivity. It is envisaged that this modelling approach will pave the model-based development of industrial cell lines and clinical studies.

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Section: Resultsmentioning

confidence: 99%

Cyclin and DNA Distributed Cell Cycle Model for GS-NS0 Cells

et al. 2015

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“…In recent years, several studies have appeared where stationary MFA was combined with a kinetic model to describe metabolic flux dynamics in batch and fed-batch cultures of CHO cells [35,107,108,[110][111][112][113]. The initial kinetic modeling framework was based a lumped network model derived from the CHO cell model by Provost and Bastin [110].…”

Section: Applications Of Mfa In Combination With a Kinetic Modelmentioning

confidence: 99%

Towards dynamic metabolic flux analysis in CHO cell cultures

Ahn

Antoniewicz

2011

Biotechnology Journal

110

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Chinese hamster ovary (CHO) cells are the most widely used mammalian cell line for biopharmaceutical production, with a total global market approaching $100 billion per year. In the pharmaceutical industry CHO cells are grown in fed-batch culture, where cellular metabolism is characterized by high glucose and glutamine uptake rates combined with high rates of ammonium and lactate secretion. The metabolism of CHO cells changes dramatically during a fed-batch culture as the cells adapt to a changing environment and transition from exponential growth phase to stationary phase. Thus far, it has been challenging to study metabolic flux dynamics in CHO cell cultures using conventional metabolic flux analysis techniques that were developed for systems at metabolic steady state. In this paper we review progress on flux analysis in CHO cells and techniques for dynamic metabolic flux analysis. Application of these new tools may allow identification of intracellular metabolic bottlenecks at specific stages in CHO cell cultures and eventually lead to novel strategies for improving CHO cell metabolism and optimizing biopharmaceutical process performance.

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“…The [11,12,51,53]. In addition, lactate is also consumed (Q Lac ) [14,55], which in this case was modelled and triggered by the depletion of glutamate.…”

Section: Cyclins Growth Functionsmentioning

confidence: 99%

A Cyclin Distributed Cell Cycle Model in GS-NS0

Munzer

Kostoglou

Georgiadis

et al. 2014

Computer Aided Chemical Engineering

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Mammalian cell cultures are intrinsically heterogeneous at different scales (molecular to bioreactor). The cell cycle is at the centre of capturing heterogeneity since it plays a critical role in the growth, death, and productivity of mammalian cell cultures. Current cell cycle models use biological variables (mass/volume/age) that are non-mechanistic, and difficult to experimentally determine, to describe cell cycle transition and capture culture heterogeneity. To address this problem, cyclins-key molecules that regulate cell cycle transitionhave been utilized. Herein, a novel integrated experimental-modelling platform is presented whereby experimental quantification of key cell cycle metrics (cell cycle timings, cell cycle fractions, and cyclin expression determined by flow cytometry) is used to develop a cyclin and DNA distributed model for the industrially relevant cell line, GS-NS0. Cyclins/DNA synthesis rates were linked to stimulatory/inhibitory factors in the culture medium, which ultimately affect cell growth. Cell antibody productivity was characterized using cell cyclespecific production rates. The solution method delivered fast computational time that renders the model's use suitable for model-based applications. Model structure was studied by global sensitivity analysis (GSA), which identified parameters with a significant effect on the model output, followed by re-estimation of its significant parameters from a control set of batch experiments. A good model fit to the experimental data, both at the cell cycle and viable cell density levels, was observed. The cell population heterogeneity of disturbed (after cell arrest) and undisturbed cell growth was captured proving the versatility of the modelling approach. Cell cycle models able to capture population heterogeneity facilitate in depth understanding of these complex systems and enable systematic formulation of culture strategies to improve growth and productivity. It is envisaged that this modelling approach will pave the model-based development of industrial cell lines and clinical studies.PLOS Computational Biology |

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Development of a mathematical model for evaluating the dynamics of normal and apoptotic Chinese hamster ovary cells

Cited by 42 publications

References 37 publications

Cyclin and DNA Distributed Cell Cycle Model for GS-NS0 Cells

Cyclin and DNA Distributed Cell Cycle Model for GS-NS0 Cells

Towards dynamic metabolic flux analysis in CHO cell cultures

A Cyclin Distributed Cell Cycle Model in GS-NS0

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