Embryonic development in mammals is generally a continuous process, but in certain species, this progression can be deliberately paused through a phenomenon known as embryonic diapause. This mechanism allows the embryo to temporarily enter a dormant state, delaying implantation in the uterus and extending pregnancy. The embryo remains free-floating during diapause, and this state can last for weeks or months until conditions become favorable for development to resume. However, the ability of human cells to undergo a similar process has been a long-standing question in developmental biology.
A recent study, led by Aydan Bulut-Karslıoğlu at the Max Planck Institute for Molecular Genetics and Nicolas Rivron at the Institute of Molecular Biotechnology (IMBA) in Vienna, provides compelling evidence that human cells may also be capable of responding to molecular signals that induce diapause. The study, published on September 26 in Cell, used advanced stem cell models to explore the molecular pathways responsible for this phenomenon.
Using Stem Cell Models to Mimic Diapause in Humans
Instead of experimenting directly on human embryos, the researchers used stem cell-derived blastocyst models known as blastoids. These blastoids mimic early embryonic development and offer an ethical and scientifically robust alternative to studying real embryos. By focusing on human stem cells and blastoids, the team investigated how modulation of a key molecular cascade—the mTOR signaling pathway—could induce a dormant, diapause-like state.
“The mTOR pathway is a major regulator of growth and developmental progression in mouse embryos,” said Bulut-Karslıoğlu. “When we treated human stem cells and blastoids with an mTOR inhibitor, we observed a developmental delay, which means that human cells can deploy the molecular machinery to elicit a diapause-like response.”
The dormant state induced in the human models exhibited hallmark features of diapause, including reduced cell division, slowed development, and decreased attachment to the uterine lining. These findings suggest that, while humans may not naturally use this mechanism during pregnancy, the cellular machinery for entering dormancy is present.
Timing and Reversibility of the Dormant State
Interestingly, this dormancy appears to be reversible. The researchers found that once the mTOR pathway was reactivated, the cells resumed normal development. However, the ability to enter this dormant state is limited to a specific period—around the blastocyst stage. As shared first author Dhanur P. Iyer noted, “The developmental timing of blastoids can be stretched around the blastocyst stage, which is exactly the stage where diapause works in most mammals.”
This transient period of dormancy raises intriguing questions about the evolutionary significance of this ability in humans. Nicolas Rivron commented, “This potential may be a vestige of the evolutionary process that we no longer make use of. Although we have lost the ability to naturally enter dormancy, these experiments suggest that we have nevertheless retained this inner ability and could eventually unleash it.”
Potential Implications for Reproductive Medicine
The study’s findings could have significant implications for assisted reproductive technologies, particularly in vitro fertilization (IVF). “On the one hand, undergoing faster development is known to increase the success rate of IVF, and enhancing mTOR activity could achieve this,” explained Rivron. “On the other hand, triggering a dormant state during an IVF procedure could provide a larger time window to assess embryo health and to synchronize it with the mother for better implantation inside the uterus.”
Beyond its practical applications, the study opens up new avenues for understanding how human cells—and mammalian cells more broadly—respond to developmental signals. Further research could explore whether different species use similar or divergent molecular pathways to pause embryonic development. Understanding these mechanisms might not only shed light on early human development but also offer clues about how cells manage growth and stress in other biological contexts.
“This exciting collaboration is a testimony to how complex biological questions can be tackled by bringing together respective expertise,” said co-first author Heidar Heidari Khoei, a postdoctoral fellow in Rivron’s lab. "I believe this work not only underscores the importance of collaboration in advancing science but also opens up further possibilities for understanding how various signals are perceived by cells as they prepare for their developmental journey.”
