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

Yilmaz, Alperen
; 
Gurhan, Gulben
; 
Comar, Mehmet-Yunus
; 
Viukov, Sergey
; 
Serfaty, Inbal
; 
Gayretli, Mert
; 
Golenchenko, Sergey
; 
Lokshtanov, Dmitry
; 
Ashouokhi, Shahd
; 
Polanco, Angel
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Author
Yilmaz, Alperen
Gurhan, Gulben
Comar, Mehmet-Yunus
Viukov, Sergey
Serfaty, Inbal
Gayretli, Mert
Golenchenko, Sergey
Lokshtanov, Dmitry
Ashouokhi, Shahd
Polanco, Angel
Berlad, Idan
Ha, Tae-Won
Aguilera-Castrejon, Alejandro
Tarazi, Shadi
Cohen, Marina
Livnat, Nir
Kumar, Komal
Cholakkal, Hisham
Levy, Nathan
Yosef, Nir
Khatib, Nizar
Kakun, Reli Rachel
Kedmi, Merav
Bolocan Nachman, Inbal
Keren-Shaul, Hadas
Addadi, Yoseph
Orenbuch, Ayelet-Hashahar
Korovin, Karina
Molchadsky, Alina
Hochedlinger, Konrad
Gafni, Ohad
Maza, Itay
Novershtern, Noa
Oldak, Bernardo
Hanna, Jacob H.
Supervisor
Department
Computer Vision
Embargo End Date
Type
Journal article
Date
2025
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Language
English
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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.
Citation
A. Yilmaz et al., “Transgene-free generation of mouse post-gastrulation whole embryo models solely from naive ESCs and iPSCs,” Cell Stem Cell, Aug. 2025, doi: 10.1016/J.STEM.2025.07.005
Source
Cell Stem Cell
Conference
Keywords
Embryo Models, Synthetic Embryology, Extra-Embryonic Lineages, Naive Pluripotency, Chemical Reprogramming, Primitive Endoderm, Trophoblast Stem Cells, Ex Utero Embryo Culture
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Source
Publisher
Elsevier
DOI
10.1016/j.stem.2025.07.005
Additional links
https://www.sciencedirect.com/science/article/pii/S1934590925002620
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