At some point in our evolution, we lost the ability to activate a reproductive mechanism called embryonic diapause, which slows development, usually during the blastocyst stage. And so, unlike mammals that have retained embryonic diapause, we are unable to suspend development, even if doing so would improve the chances of survival for both the embryo and the mother.
Yet embryonic diapause is still in our cells. And, according to scientists at the Max Planck Institute for Molecular Genetics and the Institute of Molecular Biotechnology (IMBA) at the Austrian Academy of Sciences, we may once again gain the ability to invoke it. Indeed, the ability to activate embryonic diapause could help us improve vitro fertilization (IVF).
The scientists reported their findings in Cell, in an article titled, “mTOR activity paces human blastocyst stage developmental progression.” The article describes how the scientists used stem cell models to show that modulation of a specific molecular cascade, the mTOR signaling pathway, induces a dormant state remarkably akin to diapause.
“[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,” the article’s authors wrote. “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.”
In some mammals, embryonic diapause often happens just before the embryo implants in the uterus. The embryo remains free-floating, and pregnancy is extended. This dormant state can be maintained for weeks or months before development is resumed, when conditions are favorable.
Mammals known to have lost the ability to activate this reproductive mechanism can still have it triggered experimentally. For example, sheep blastocysts that do not naturally diapause can enter this dormant state upon transfer into mouse uteri induced for diapause. But could human cells respond to diapause triggers? This question remained unresolved before the current study, which was carried out by scientists led by Aydan Bulut-Karslıoğlu, PhD, at Max Planck and Nicolas Rivron, PhD, at IMBA.
The scientists succeeded in identifying the molecular mechanisms that control embryonic diapause, which seem to be actionable in human cells. In their research, the scientists did not carry out experiments on human embryos and instead used human stem cells and stem cell-based blastocyst models called blastoids. These blastoids are a scientific and ethical alternative to using embryos for research.
The researchers discovered that modulation of a specific molecular cascade, the mTOR signaling pathway, in these stem cell models induces a dormant state remarkably akin to diapause. “The mTOR pathway is a major regulator of growth and developmental progression in mouse embryos,” said Bulut-Karslioglu. “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.”
This dormant state is characterized by reduced cell division, slower development, and a decreased ability to attach to the uterine lining. Importantly, the capacity to enter this dormant stage seems to be restricted to a brief developmental period.
“The developmental timing of blastoids can be stretched around the blastocyst stage, which is exactly the stage where diapause works in most mammals,” said co-first author Dhanur P. Iyer, a PhD student at Max Planck. Moreover, this dormancy is reversible, and blastoids resume normal development when the mTOR pathway is reactivated.
The authors concluded that humans, like other mammals, might possess an inherent mechanism to temporarily slow down their development, even though this mechanism may not be used during pregnancy. “This potential may be a vestige of the evolutionary process that we no longer make use of,” said Rivron. “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.” For basic research, the question arises as to whether human and other mammalian cells enter the dormant state via similar or alternative pathways and use it for the same purposes, for example, either pausing or timing their development and implantation.
The team’s discoveries could have implications for reproductive medicine: “On the one hand, undergoing faster development is known to increase the success rate of IVF, and enhancing mTOR activity could achieve this,” Rivron explained. “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.”
Overall, the new findings provide unforeseen insights into the processes governing our earliest development, which might open new avenues for enhancing reproductive health. “This exciting collaboration is a testimony to how complex biological questions can be tackled by bringing together respective expertise,” said Heidar Heidari Khoei, PhD, a postdoctoral fellow in Rivron’s lab and the study’s co-first author. “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.”
