PluriMetNet: A dynamic electronic model decrypting the metabolic variations in human embryonic stem cells (hESCs) at fluctuating oxygen concentrations

Stem cells are an excellent resource in translational medicine however much is known only in terms of transcriptional and epigenetic regulation of human embryonic stem cells (hESCs). Metabolic regulation of hESCs is still unexplored in many ways, particularly the role of energy metabolism, which is intrinsic to the maintenance of cell viability, however, is very little explored in the past years. Also, there exists no hESC specific core metabolic model of pluripotency as per our knowledge. Through our work, we establish such a metabolic model of hESC using combinatorial in-silico approach of genome scale model reduction and literature curation. Further, through perturbations taking oxygen as a parameter we propose that under lower levels of oxygen concentration there is a significant dynamic change in the energy metabolism of the hESC. We further investigated energy subsystem pathways and their respective reactions in order to locate the direction of energy production along with the dynamic of nutrient metabolites like glucose and glutamine. The output shows a steep increment/decrement at a certain oxygen range. These sharp increments/decrements under hypoxic conditions are termed here as a critical range for hESC metabolic pathway. The data also resonates with the previous experimental studies on hESC energy metabolism confirming the robustness of our model. The model helps to extract range for different pathways in the energy subsystem, making us a little closer in understanding the metabolism of hESC. We also demonstrated the possible range of pathway changes in hESC's energy metabolism that can serve as the crucial preliminary data for further prospective studies. The model also offers a promise in the prediction of the flux behaviour of various metabolites in hESC. Communicated by Ramaswamy H. Sarma