Researchers have found a possible ‘pause button’ in the initial stages of human development. The question of whether humans can control their developmental timing has been a subject of ongoing debate. This new study implies that this ‘pause button’ can actually be activated in human cells too. These findings are crucial for enhancing our comprehension of early human life and may lead to advancements in reproductive technologies.
Researchers at the Max Planck Institute for Molecular Genetics and the Institute of Molecular Biotechnology (IMBA), part of the Austrian Academy of Sciences, have identified a potential “pause button” during the very early phases of human development. The ability of humans to regulate their developmental timing has been a long-standing discussion. The recent research indicates that this “pause button” can also be triggered in human cells. This discovery holds great importance for our understanding of early human life and could advance reproductive technologies.
In some mammals, the timing of normal, continuous embryonic development can be adjusted to enhance the survival prospects of both the embryo and the mother. This temporary slowing down of development, known as embryonic diapause, typically occurs at the blastocyst stage, right before the embryo implants in the uterus. During diapause, the embryo floats freely, extending the pregnancy duration. This inactive condition can last for weeks or months until conditions become favorable for development to resume. Although not all mammals utilize this reproductive strategy, it is possible to experimentally trigger the ability to pause development. However, it remained uncertain if human cells could respond similarly to diapause triggers.
Now, a study conducted by Aydan Bulut-KarslioÄŸlu at the Max Planck Institute for Molecular Genetics in Berlin and Nicolas Rivron at IMBA, an ERC grantee in Vienna, has revealed that the molecular mechanisms controlling embryonic diapause appear to be applicable to human cells. The results of their study were published on September 26th in the journal Cell.
Utilizing stem cell-derived models to investigate embryonic diapause in humans
In their investigation, the researchers did not experiment with human embryos but instead utilized human stem cells and stem cell-derived blastocyst models, known as blastoids. These blastoids provide a scientific and ethical alternative for research without using actual embryos. The scientists found that by altering a specific molecular pathway, the mTOR signaling pathway, in these stem cell models, they could induce a dormant state remarkably similar to diapause. “The mTOR pathway is a critical regulator of growth and developmental progression in mouse embryos,” remarks Aydan Bulut-KarslioÄŸlu. “When we administered an mTOR inhibitor to human stem cells and blastoids, we noticed a developmental delay, demonstrating that human cells can indeed activate the molecular mechanisms necessary for a diapause-like response.”
This dormant state is characterized by reduced cell division, slower development, and a diminished ability to adhere to the uterine lining. Significantly, the ability to enter this dormant state appears to be limited to a specific developmental window. “The timing of development in blastoids can be temporarily extended around the blastocyst stage, which is precisely the point where diapause occurs in most mammals,” explains shared first author Dhanur P. Iyer. Furthermore, this dormant state is reversible; blastoids can resume normal development once the mTOR pathway is reactivated.
The potential to modify the timing of embryonic development has implications for IVF
The researchers concluded that, similar to other mammals, humans may possess a natural mechanism for temporarily slowing down their development, even if this mechanism is not utilized during pregnancy. “This potential might be a remnant of evolutionary processes that we no longer engage with,” suggests Nicolas Rivron. “Although we may have lost the ability to naturally enter dormancy, these experiments indicate that we still retain this intrinsic ability, which could eventually be harnessed.” For fundamental research, an important question arises: do human and other mammalian cells enter this inactive state through the same or different pathways, and do they utilize it for similar purposes, such as pausing or timing their development and implantation?
The team’s findings could have meaningful repercussions for reproductive medicine: “On one hand, accelerating development is known to improve the success rates of in vitro fertilization (IVF), and boosting mTOR activity could help achieve this,” Nicolas Rivron notes. “On the other hand, inducing a dormant state during an IVF process may allow for a broader time frame to evaluate embryo health and synchronize it with the mother’s body for better implantation in the uterus.”
Overall, these new discoveries provide valuable insights into the processes that influence our earliest stages of development, potentially paving the way for improvements in reproductive health. “This exciting collaboration exemplifies how complex biological questions can be addressed through combined expertise,” says Heidar Heidari Khoei, a postdoctoral fellow in Nicolas Rivron’s lab and one of the study’s co-first authors. “I believe this work highlights the significance of collaboration in advancing science and opens up further opportunities to understand how various signals are interpreted by cells as they prepare for their developmental journey.”
Nicolas Rivron is a group leader at IMBA and is supported by an ERC Consolidator Grant.
