Naïve pluripotency can be established in human pluripotent stem cells (hPSCs) by manipulation of transcription factors, signaling pathways, or a combination thereof. However, differences exist in the molecular and functional properties of naïve hPSCs generated by different protocols, which include varying similarities with pre‐implantation human embryos, differentiation potential, and maintenance of genomic integrity. We show here that short treatment with two chemical agonists (2a) of nuclear receptors, liver receptor homologue‐1 (LRH‐1) and retinoic acid receptor gamma (RAR‐γ), along with 2i/LIF (2a2iL) induces naïve‐like pluripotency in human cells during reprogramming of fibroblasts, conversion of pre‐established hPSCs, and generation of new cell lines from blastocysts. 2a2iL‐hPSCs match several defined criteria of naïve‐like pluripotency and contribute to human–mouse interspecies chimeras. Activation of TGF‐β signaling is instrumental for acquisition of naïve‐like pluripotency by the 2a2iL induction procedure, and transient activation of TGF‐β signaling substitutes for 2a to generate naïve‐like hPSCs. We reason that 2a2iL‐hPSCs are an easily attainable system to evaluate properties of naïve‐like hPSCs and for various applications.

中文翻译：

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人多能干细胞中 LRH-1 和 RAR-γ 的时间激活诱导功能性幼稚状态

通过操纵转录因子、信号通路或其组合，可以在人类多能干细胞 (hPSC) 中建立幼稚多能性。然而，不同方案产生的初始 hPSC 的分子和功能特性存在差异，包括与植入前人类胚胎的不同相似性、分化潜力和基因组完整性的维持。我们在此表明​​，用两种核受体化学激动剂 (2a)、肝受体同源物-1 (LRH-1) 和视黄酸受体 γ (RAR-γ) 以及 2i/LIF (2a2iL) 进行短期治疗会诱导幼稚样在成纤维细胞重编程、预先建立的 hPSC 转化以及从囊胚产生新细胞系期间人类细胞的多能性。2a2iL-hPSCs 符合几个定义的类似幼稚多能性的标准，并有助于人-小鼠种间嵌合体。TGF-β 信号的激活有助于通过 2a2iL 诱导程序获得类似幼稚的多能性，并且 TGF-β 信号的瞬时激活替代 2a 以产生类似幼稚的 hPSC。我们认为 2a2iL-hPSCs 是一种易于获得的系统，可以评估幼稚 hPSCs 的特性和各种应用。