Capture of Mouse and Human Stem Cells with Features of Formative Pluripotency - PubMed (nih.gov)

摘要

Pluripotent cells emerge as a naive founder population in the blastocyst, acquire capacity for germline and soma formation, and then undergo lineage priming. Mouse embryonic stem cells (ESCs) and epiblast-derived stem cells (EpiSCs) represent the initial naive and final primed phases of pluripotency, respectively. Here, we investigate the intermediate formative stage. Using minimal exposure to specification cues, we derive stem cells from formative mouse epiblast. Unlike ESCs or EpiSCs, formative stem (FS) cells respond directly to germ cell induction. They colonize somatic tissues and germline in chimeras. Whole-transcriptome analyses show similarity to pre-gastrulation formative epiblast. Signal responsiveness and chromatin accessibility features reflect lineage capacitation. Furthermore, FS cells show distinct transcription factor dependencies, relying critically on Otx2. Finally, FS cell culture conditions applied to human naive cells or embryos support expansion of similar stem cells, consistent with a conserved staging post on the trajectory of mammalian pluripotency.
多能細(xì)胞在胚泡中作為naive的創(chuàng)始群體出現(xiàn)，獲得種系和體細(xì)胞形成的能力，然后進(jìn)行譜系啟動(dòng)。小鼠胚胎干細(xì)胞 (ESCs) 和上胚層衍生干細(xì)胞 (EpiSCs) 分別代表多能性的初始naive期和最終primed期。在這里，我們研究了中間formative階段。使用最少的分化誘導(dǎo)信號(hào)，我們從formative小鼠上胚層中提取干細(xì)胞。與 ESC 或 EpiSC 不同，formative stem (FS) 細(xì)胞直接響應(yīng)生殖細(xì)胞誘導(dǎo)信號(hào)。它們在嵌合體中定殖體細(xì)胞組織和種系。全轉(zhuǎn)錄組分析顯示與原腸胚形成前的上胚層相似。信號(hào)響應(yīng)性和染色質(zhì)可及性特征反映了譜系獲能。此外，F(xiàn)S 細(xì)胞表現(xiàn)出明顯的轉(zhuǎn)錄因子依賴性，嚴(yán)重依賴 Otx2。最后，應(yīng)用于人類naive細(xì)胞或胚胎的 FS 細(xì)胞培養(yǎng)條件支持相似干細(xì)胞的擴(kuò)增，這與哺乳動(dòng)物多能性軌跡上的保守階段一致。

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