Metabolic Regulatory Network Kinetic Modeling with Multiple Isotopic Tracers for iPSCs

TL;DR

This paper presents a kinetic model of iPSC metabolism using isotopic tracers, enabling prediction of cellular responses to environmental changes and supporting process control for regenerative medicine manufacturing.

Contribution

A comprehensive metabolic kinetic model for iPSCs incorporating multiple pathways and isotopic data, advancing understanding and control of cell culture processes.

Findings

Model accurately predicts cellular metabolic responses.

Supports optimization of culture conditions.

Facilitates large-scale regenerative medicine manufacturing.

Abstract

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