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The rapidly expanding market for regenerative medicines and cell therapieshighlights the need to advance the understanding of cellular metabolisms andimprove the prediction of cultivation production process for human inducedpluripotent stem cells (iPSCs). In this paper, a metabolic kinetic model wasdeveloped to characterize underlying mechanisms of iPSC culture process, whichcan predict cell response to environmental perturbation and support processcontrol. This model focuses on the central carbon metabolic network, includingglycolysis, pentose phosphate pathway (PPP), tricarboxylic acid (TCA) cycle,and amino acid metabolism, which plays a crucial role to support iPSCproliferation. Heterogeneous measures of extracellular metabolites and multipleisotopic tracers collected under multiple conditions were used to learnmetabolic regulatory mechanisms. Systematic cross-validation confirmed themodel's performance in terms of providing reliable predictions on cellularmetabolism and culture process dynamics under various culture conditions. Thus,the developed mechanistic kinetic model can support process control strategiesto strategically select optimal cell culture conditions at different times,ensure cell product functionality, and facilitate large-scale manufacturing ofregenerative medicines and cell therapies.

Metabolic Regulatory Network Kinetic Modeling with Multiple Isotopic Tracers for iPSCs