魏茨曼科学研究所Jacob H. Hanna团队提出了用未成熟的ESCs和iPSCs制备小鼠原肠胚后全胚胎模型。2025年8月7日出版的《细胞—干细胞》发表了这项成果。

该课题组证明，通过信号通路调节，无主题nESCs和幼稚诱导多能干细胞（niPSCs）可以同时共诱导产生PrE和TE胚外细胞，这些细胞可以自组织成胚日(E) 8.5-E8.75无转基因（TF）的SEMs。研究团队还设计了一种替代条件（AC）初始培养基，该培养基在体外稳定TF-SEM诱导的OCT4+/NANOG+ nESC集落，这些集落共同表达拮抗CDX2和/或GATA6胚外命运主调控因子，并在保持TE和PrE分化的同时自我更新。这些发现改善了母位扫描电镜策略，并阐明了在体外扩增母位幼稚多能细胞固有的和休眠的胚胎外可塑性。

据悉，完全由原始胚胎干细胞（nESCs）产生的原肠胚后干细胞衍生的同主题胚胎模型（SEMs）强调了它们产生胚胎和胚胎外谱系的能力。然而，现有的多主题SEMs方案依赖于单独诱导胚胎外谱系和转录因子的异位表达来诱导nESC分化为滋养外胚层（TE）或原始内胚层（PrE）。

附：英文原文

Title: Transgene-free generation of mouse post-gastrulation whole embryo models solely from naive ESCs and iPSCs

Author: Alperen Yilmaz, Gulben Gurhan, Mehmet-Yunus Comar, Sergey Viukov, Inbal Serfaty, Mert Gayretli, Sergey Golenchenko, Dmitry Lokshtanov, Shahd Ashouokhi, Angel Polanco, Idan Berlad, Tae-Won Ha, Alejandro Aguilera-Castrejon, Shadi Tarazi, Marina Cohen, Nir Livnat, Komal Kumar, Hisham Cholakkal, Nathan Levy, Nir Yosef, Nizar Khatib, Reli Rachel Kakun, Merav Kedmi, Inbal Bolocan Nachman, Hadas Keren-Shaul, Yoseph Addadi, Ayelet-Hashahar Orenbuch, Karina Korovin, Alina Molchadsky, Konrad Hochedlinger, Ohad Gafni, Itay Maza, Noa Novershtern, Bernardo Oldak, Jacob H. Hanna

Issue&Volume: 2025-08-07

Abstract: The generation of post-gastrulation stem cell-derived mouse embryo models (SEMs) exclusively from naive embryonic stem cells (nESCs) has underscored their ability to give rise to embryonic and extra-embryonic lineages. However, existing protocols for mouse SEMs rely on the separate induction of extra-embryonic lineages and on ectopic expression of transcription factors to induce nESC differentiation into trophectoderm (TE) or primitive endoderm (PrE). Here, we demonstrate that mouse nESCs and naive induced pluripotent stem cells (niPSCs) can be simultaneously co-induced, via signaling pathway modulation, to generate PrE and TE extra-embryonic cells that self-organize into embryonic day (E) 8.5–E8.75 transgene-free (TF) SEMs. We also devised an alternative condition (AC) naive media that in vitro stabilizes TF-SEM-competent OCT4+/NANOG+ nESC colonies that co-express antagonistic CDX2 and/or GATA6 extra-embryonic fate master regulators and self-renew while remaining poised for TE and PrE differentiation, respectively. These findings improve mouse SEM strategies and shed light on amplifying an inherent and dormant extra-embryonic plasticity of mouse naive pluripotent cells in vitro.

DOI: 10.1016/j.stem.2025.07.005

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(25)00262-0