Abstract
Human induced pluripotent cells (hiPSCs), generated in vitro, represent a groundbreaking tool for tissue regeneration and repair. Understanding the metabolic intricacies governing hiPSCs is crucial for optimizing their performance across diverse environmental conditions and improving production strategies. To this end, in this work, we introduce hiPSCGEM01, the first genome-scale, context-specific metabolic model (GEM) uniquely tailored to fibroblast-derived hiPSCs, marking a clear distinction from existing models of embryonic and cancer stem cells. hiPSCGEM01 was developed using relevant genome expression data carefully selected from the Gene Expression Omnibus (GEO), and integrated with the RECON 3D framework, a comprehensive genome-scale metabolic model of human metabolism. Redundant and unused reactions and genes were identified and removed from the model. Key reactions, including those facilitating the exchange and transport of metabolites between extracellular and intracellular environments, along with all metabolites required to simulate the growth medium, were integrated into hiPSCGEM01. Finally, blocked reactions and dead-end metabolites were identified and adequately solved. Knockout simulations combined with flux balance analysis (FBA) were employed to identify essential genes and metabolites within the metabolic network, providing a comprehensive systems-level view of fibroblast-derived hiPSC metabolism. Notably, the model uncovered the unexpected involvement of nitrate and xenobiotic metabolism-pathways not previously associated with hiPSCs-highlighting potential novel mechanisms of cellular adaptation that merit further investigation. hiPSCGEM01 establishes a robust platform for in silico analysis and the rational optimization of in vitro experiments. Future applications include the evaluation and refinement of culture media, the design of new formulations, and the prediction of hiPSC responses under varying growth conditions, ultimately advancing both experimental and clinical outcomes.