Summary Human pluripotent stem cells (hPSCs) can self-organize into a blastocyst-like structure (blastoid) by virtue of their full developmental potential. The pluripotent mouse embryonic stem cells (mESC) are considered to lack this potential and hence can form blastoids only when combined with trophoblast stem cells. We performed a small molecule and cytokine screen to demonstrate that mESC have full potential to efficiently self-organize themselves into E-blastoids (ESC-blastoids). The morphology, cell lineages and the transcriptome of these blastoids resemble the mouse blastocyst. The E-blastoids undergo implantation and in utero development in mice. The transient reactivation of the 2C-gene network by retinoid signaling is essential for E-blastoid generation. GSK3β activity is critical for retinoid signaling and consequent 2C gene network activation. Collectively, the mESC possess full developmental potential to generate blastoids similar to hPSCs and other mammals. The plasticity of PSCs to self-organize into blastoids is not exclusive to humans or larger mammals; rather, it could be a general feature shared by most mammals, including rodents.

Efficient self-organization of blastoids solely from mouse ESCs is facilitated by transient reactivation of 2C gene network