(724e) Lactate Metabolism in Cell Culture Processes: Model Prediction of the Trajectory to Lactate Consumption

Mammalian cells in culture consume glucose and produce a large quantity of lactate. However, under certain culture conditions, glucose flux decreases and the metabolism shifts to lactate consumption. The transition to lactate consumption has been associated with an enhanced productivity as evidence by mining a trove of process data. However, the shift of metabolism is elusive in nature; under similar conditions some cultures metabolically shift to lactate consumption state while others continue to produce lactate. A mechanistic kinetic model based on reactions in glycolysis, pentose phosphate pathway and TCA cycle was developed. The allosteric regulations, acting on the various glycolysis isozymes, together form regulatory loops that give rise to a multiplicity of states in the glycolytic behavior.  Such a behavior is profoundly affected by culture lactate levels as well as cell growth rate resulting is a complex topology of the steady state fluxes, in a multi-dimensional space.  The switch from the lactate production state to the consumption state can occur only at a certain region in the steady state topology. To further understand such complex behavior, the model was used to simulate the transient behavior in the critical period of metabolic shift and compared to the trajectories of the runs in the archived data. Insights on how to achieve a control of cell metabolism will be presented.