A dynamic model linking cell growth to intracellular

metabolism and extracellular by‐product accumulation

João R. C. Ramos, Alexander G. Rath, Yvonne Genzel, Volker Sandig, Udo Reichl

doi: 10.1002/bit.27288

Abstract

Mathematical modeling of animal cell growth and metabolism is essential for the
understanding and improvement of the production of biopharmaceuticals. Models can
explain the dynamic behavior of cell growth and product formation, support the
identification of the most relevant parameters for process design, and significantly reduce
the number of experiments to be performed for process optimization. Few dynamic
models have been established that describe both extracellular and intracellular dynamics
of growth and metabolism of animal cells. In this study, a model was developed, which
comprises a set of 33 ODEs to describe batch cultivations of suspension AGE1.HN.AAT
cells considered for the production of alpha1‐antitrypsin. This model combines a
segregated cell growth model with a structured model of intracellular metabolism. Overall,
it considers the viable cell concentration, mean cell diameter, viable cell volume,
concentration of extracellular substrates, and intracellular concentrations of key
metabolites from the central carbon metabolism. Furthermore, the release of metabolic
by‐products such as lactate and ammonium was estimated directly from the intracellular
reactions. Based on the same set of parameters, this model simulates well the dynamics
of four independent batch cultivations. Analysis of the simulated intracellular rates
revealed at least two distinct cellular physiological states. The first physiological state was
characterized by a high glycolytic rate and high lactate production. Whereas the second
state was characterized by efficient ATP production, a low glycolytic rate, and reactions
of the TCA cycle running in the reverse direction from alpha‐ketoglutarate to citrate.
Finally, we show possible applications of the model for cell line engineering and media
optimization with two case studies.

Keywords
Animal cell; dynamic model; glycolysis; kinetic; metabolism; TCA cycle
Article PDF:
https://doi.org/10.1002/bit.27288