ERRs Mediate a Metabolic Switch Required for Somatic Cell Reprogramming. Mus musculus strain:C57Bl/6

We show that key regulators of oxidative metabolism, the Estrogen Related Receptors (ERRs) and the PGC-1 co-activators, are transiently induced during somatic cell reprogramming. Bioenergetic assays reveal that while glycolysis increases throughout the reprogramming transition, the early stages feature a transient oxidative phosphorylation (OXPHOS) burst. Up-regulation of ERRα or γ is a prerequisite for the OXPHOS burst in human and mouse cells, respectively, and failure to induce this metabolic switch collapses the reprogramming process. We identify a Sca1-/CD34- sub-population of early reprogramming cells with enhanced ERRγ and PGC-1β expression as bona fide reprogramming progenitors. Transcriptional profiling confirmed that these progenitors have undergone extensive metabolic reprogramming. These studies characterize a previously unrecognized, ERR-dependent metabolic switch prior to establishment of induced pluripotency.

本研究表明，氧化代谢的关键调控因子——雌激素相关受体（Estrogen Related Receptors，ERRs）与PGC-1辅激活因子（PGC-1 co-activators），在体细胞重编程过程中会被瞬时诱导表达。生物能学检测结果显示，尽管在整个重编程进程中糖酵解水平持续升高，但早期阶段会出现一过性的氧化磷酸化（oxidative phosphorylation，OXPHOS）爆发。ERRα与ERRγ的上调分别是人源和鼠源细胞中OXPHOS爆发的必要前提，若无法诱导该代谢转换，则会导致重编程过程失败。本研究鉴定出一群Sca1-/CD34-的早期重编程细胞亚群，该亚群中ERRγ与PGC-1β的表达水平升高，属于确凿的重编程祖细胞。转录谱分析证实，这些祖细胞已经发生了广泛的代谢重编程。本研究阐明了诱导多能性建立之前，一种此前未被发现的、依赖ERR的代谢转换机制。