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

干细胞是转化医学领域的优质研究资源，但目前学界对人类胚胎干细胞（human embryonic stem cells, hESCs）的认知多局限于其转录调控与表观遗传调控机制。然而，人类胚胎干细胞的代谢调控仍存在诸多未被阐明的环节，其中与细胞活力维持密切相关的能量代谢调控，在过往数年中的研究尤为匮乏。据我们所知，目前尚无针对人类胚胎干细胞多能性的特异性核心代谢模型。本研究通过结合基因组规模模型缩减与文献整理的计算机模拟方法，构建了首个人类胚胎干细胞代谢模型。进一步以氧浓度为扰动参数开展模拟实验，我们发现：当氧浓度处于较低水平时，人类胚胎干细胞的能量代谢会发生显著的动态变化。我们还对能量子系统通路及其对应反应进行了深入分析，以明确能量产生的方向以及葡萄糖、谷氨酰胺等营养代谢物的动态变化规律。结果显示，在特定氧浓度区间内，代谢物水平会出现急剧的升高或降低。我们将低氧条件下的这类剧烈波动定义为人类胚胎干细胞代谢通路的"临界氧浓度区间"。该模型的预测结果与既往人类胚胎干细胞能量代谢的实验研究相符，验证了模型的稳健性。本模型可用于提取能量子系统各通路的活性区间，有助于我们进一步深化对人类胚胎干细胞代谢机制的理解。此外，我们还明确了人类胚胎干细胞能量代谢通路的潜在变化区间，可为后续前瞻性研究提供关键的前期数据支撑。该模型还可用于预测人类胚胎干细胞中多种代谢物的通量行为。本文由Ramaswamy H. Sarma提交。