mTOR activity paces human blastocyst stage developmental progression

Many mammals can temporally uncouple conception from parturition by pacing down their development around the blastocyst stage. In mice, this dormant state is achieved by decreasing the activity of the growth-regulating mTOR signaling pathway. It is unknown whether this ability is conserved in mammals in general and in humans in particular. Here, we show that decreasing the activity of the mTOR signaling pathway induces human pluripotent stem cells (hPSCs) and blastoids to enter a dormant state with limited proliferation, developmental progression, and capacity to attach to endometrial cells. These in vitro assays show that, similar to other species, the ability to enter dormancy is active in human cells around the blastocyst stage and is reversible at both functional and molecular levels. The pacing of human blastocyst development has potential implications for reproductive therapies. [Display omitted] •Human pluripotent cells are capable of entering a reversible dormant state•Human blastoids under mTOR inhibition show a diapause-like response•Dormant human blastoids show altered developmental progression and attachment•Species-specific metabolic profiles of mouse and human cells can be seen in dormancy The timing of human blastoid post-implantation development can be paced down by inhibition of mTOR, which elicits a tissue-specific response similar to mouse in vivo diapause.