Capture of Mouse and Human Stem Cells with Features of Formative Pluripotency

Cell stem cell Pub Date : 2020-09-04 DOI:10.1101/2020.09.04.283218

Masaki Kinoshita, Michael Barber, William Mansfield, Yingzhi Cui, D. Spindlow, G. Stirparo, S. Dietmann, J. Nichols, Austin G Smith

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引用次数: 123

Abstract

Pluripotent cells emerge via a naïve founder population in the blastocyst, acquire capacity for germline and soma formation, and then undergo lineage priming. Mouse embryonic stem (ES) cells and epiblast stem cells (EpiSCs) represent the initial naïve and final primed phases of pluripotency, respectively. Here we investigate the intermediate formative stage. Using minimal exposure to specification cues, we expand stem cells from formative mouse epiblast. Unlike ES cells or EpiSCs, formative stem (FS) cells respond directly to germ cell induction. They colonise chimaeras including the germline. Transcriptome analyses show retained pre-gastrulation epiblast identity. Gain of signal responsiveness and chromatin accessibility relative to ES cells reflect lineage capacitation. FS cells show distinct transcription factor dependencies from EpiSCs, relying critically on Otx2. Finally, FS cell culture conditions applied to human naïve cells or embryos support expansion of similar stem cells, consistent with a conserved attractor state on the trajectory of mammalian pluripotency.

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具有形成性多能性特征的小鼠和人干细胞的捕获

多能干细胞通过胚泡中天真的创始人群体出现，获得种系和胞体形成的能力，然后进行谱系启动。小鼠胚胎干细胞（ES）和成表干细胞（EpiSC）分别代表多能性的初始幼稚期和最终启动期。在这里我们研究中间形成阶段。使用最小限度的暴露于特定线索，我们从形成性小鼠表皮母细胞中扩增干细胞。与ES细胞或表观干细胞不同，形成性干细胞直接对生殖细胞诱导作出反应。它们在包括种系在内的嵌合体中定植。转录组分析显示保留了原肠胚形成前表皮母细胞的特性。相对于ES细胞，信号反应性和染色质可及性的增加反映了谱系获能。FS细胞表现出与EpiSC不同的转录因子依赖性，严重依赖Otx2。最后，应用于人类幼稚细胞或胚胎的FS细胞培养条件支持类似干细胞的扩增，这与哺乳动物多能性轨迹上的保守吸引子状态一致。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Cell stem cell

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