Stem cell models of early preimplantation human embryos have been shown to retain the capacity to pause development, using a mechanism observed in other mammals.
This collaborative study, led by researchers from the Max Planck Institute for Molecular Genetics in Berlin, Germany, and the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences in Vienna, Austria, aimed to discover if human cells are capable of regulating their developmental timing at the blastocyst stage, before implantation in the uterus. Acknowledging the difficulty of studying this stage in human embryos, due to the large number of embryos required to reach statistically relevant conclusions, authors used pluripotent stem cells and stem cell-based embryo models (SCBEMs) to test whether previous findings in mice were also true in humans.
'This exciting collaboration is a testimony to how complex biological questions can be tackled by bringing together respective expertise,' said Dr Heidar Heidari Khoei, post-doctoral researcher at the IMBA and co-first author of the study published in Cell.
The ability to slow down development or enter a dormancy state is called 'embryonic diapause'. More than 130 mammalian species, from mouse to roe deer, have been shown to enter reversible diapause during their reproductive cycle. In this paused state, proliferation is limited and implantation is delayed improving the chances of survival in adverse conditions such as starvation or cold temperatures. Embryos maintain the competency to develop and respond to reactivation cues while decreasing the capacity to attach to endometrial cells, the ones responsible for implantation in the uterus.
The authors of the study had previously shown that diapause can be induced in mouse embryos by regulating the activity of the mTOR signalling pathway. In their new study, they addressed whether human cells could be triggered to slow down development in the same manner, using human pluripotent stem cells and blastoids as proxy in their experiments.
Blastoids are SCBEMs that self-assemble under precise culture conditions and have been characterised as bearing close resemblance – in certain respects – to preimplantation embryos (see BioNews 1020, 1088, 1091, 1124, 1204). They can successfully attach to uterine cells in vitro.
'The developmental timing of blastoids can be stretched around the blastocyst stage, which is exactly the stage where diapause works in most mammals,' said Dhanur Iyer, PhD student at the Max Planck Institute and co-first author of the study.
Dr Aydan Bulut-Karslioglu, research group leader at the Max Planck Institute and co-senior author of the study explained: '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 authors show that human pluripotent stem cells and blastoids can enter a diapause-like dormant state in response to mTOR inhibition, which – in vitro – lasts a maximum of eight days. They conclude that understanding the ability to speed up or slow down development at this stage could translate into better outcomes in 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,' explained Dr Nicolas Rivron, who leads the laboratory for synthetic mammalian development at the IMBA and is co-senior author of the study. 'On the other hand, triggering a dormant state during an IVF procedure could provide a larger time window to assess embryo health and to synchronise it with the mother for better implantation inside the uterus.'
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