Physiological oxygen culture reveals retention of metabolic memory in human induced pluripotent stem cells

Reprogramming somatic cells to a pluripotent cell state (induced Pluripotent Stem (iPS) cells) requires reprogramming of metabolism to support cell proliferation and pluripotency, most notably changes in carbohydrate turnover that reflect a shift from oxidative to glycolytic metabolism. Some aspects of iPS cell metabolism differ from embryonic stem (ES) cells, which may reflect a parental cell memory, or be a consequence of the reprogramming process. In this study, we compared the metabolism of 3 human iPS cell lines to assess the fidelity of metabolic reprogramming. When challenged with reduced oxygen concentration, ES cells have been shown to modulate carbohydrate use in a predictably way. In the same model, 2 of 3 iPS cell lines failed to regulate carbohydrate metabolism. Oxygen is a well-characterized regulator of cell function and embryo viability, and an inability of iPS cells to modulate metabolism in response to oxygen may indicate poor metabolic fidelity. As metabolism is linked to the regulation of the epigenome, assessment of metabolic responses of iPS cells to physiological stimuli during characterization is warranted to ensure complete cell reprogramming and as a measure of cell quality.

将体细胞重编程至多能细胞状态，即诱导多能干细胞（induced Pluripotent Stem (iPS) cells），需要对代谢进行重编程以支持细胞增殖与多能性，其中最显著的特征为碳水化合物周转发生改变，这反映了细胞代谢从氧化代谢向糖酵解代谢的转变。诱导多能干细胞的部分代谢特征与胚胎干细胞（embryonic stem (ES) cells）存在差异，这类差异可能源于亲本细胞的记忆效应，或是重编程过程本身所导致的结果。本研究中，我们对3株人源诱导多能干细胞系的代谢特征进行了比较，以评估代谢重编程的保真度。已有研究证实，当胚胎干细胞暴露于低氧环境时，能够以可预测的方式调控碳水化合物的利用。在相同的实验模型中，3株诱导多能干细胞系中有2株无法正常调控碳水化合物代谢。氧气是调控细胞功能与胚胎存活的经典调控因子，若诱导多能干细胞无法响应氧浓度变化调节代谢，则提示其代谢保真度不佳。由于代谢与表观基因组的调控密切相关，因此在细胞鉴定过程中，评估诱导多能干细胞对生理刺激的代谢响应，对于确保细胞完全重编程以及衡量细胞质量均具有必要性。