A stem cell-based approach for modelling implantation in vitro

Project Information

IMPLANTATION

Grant agreement ID: 101026451

DOI

10.3030/101026451

Project closed

EC signature date 30 April 2021

Start date 1 September 2022

End date 31 August 2024

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 174 167,04

EU contribution

€ 174 167,04

Coordinated by

INSTITUT FUER MOLEKULARE BIOTECHNOLOGIE GMBH
Austria

Periodic Reporting for period 1 - IMPLANTATION (A stem cell-based approach for modelling implantation in vitro)

Reporting period: 2022-09-01 to 2024-08-31

Summary of the context and overall objectives of the project

This research investigates the early stages of human embryo development and implantation, focusing on developing realistic stem cell-based models of human blastocyst. Human embryo implantation remains challenging to study due to the embryo's small size and the inaccessibility of implantation processes within the womb. By developing “human blastoids” from stem cells, we can now replicate key early stages of embryo development and implantation in a dish, enabling detailed exploration of this complex biological process.
Understanding implantation is essential for improving reproductive health. This knowledge can directly enhance infertility treatments, particularly in optimizing in vitro fertilization (IVF) procedures, giving greater hope to couples facing fertility challenges. Moreover, these insights can guide the development of new contraceptive options and may even contribute to reducing the risk of chronic conditions linked to reproductive health.
The main objectives of this project were to establish a reliable, scalable model for studying human embryo implantation and to identify molecular mechanisms, like the mTOR signaling pathway, that influence embryo development timing and attachment. This work has led to the discovery that inhibiting mTOR activity can put human cells in a dormant state, slowing their development—a feature seen in some animals but now observed in human cells. The blastoid model enables new ways to study implantation and supports further investigation into reproductive biology. Ultimately, these findings have broad implications for fertility treatments, contraceptive development, and the future of reproductive health.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

From the start of the project, the project focused on generating human “blastoids” from stem cells, and modeling their interaction with endometrial cells. These blastoids provided a model to study the cellular organization and molecular interactions essential for embryo implantation, a process typically challenging to observe directly in humans. We utilized advanced stem cell culture techniques to efficiently produce blastoids, containing the key cell lineages needed for implantation.
Additionally, a parallel investigation explored the effect of mTOR signaling on early development and implantation, revealing that by inhibiting mTOR activity, human blastoids could enter a reversible dormant state. Through these experiments, we identified how human manage developmental pacing, highlighting new avenues for reproductive research.

Main Results Achieved
The main accomplishments include:

Establishment of human blastoids as a research model and studying implantation: Blastoids were successfully developed from stem cells and demonstrated characteristics closely resembling natural human blastocysts. This breakthrough offers a scalable and ethical model to investigate implantation and early embryo development, laying the groundwork for future applications in fertility and contraception research.

Discovery of mTOR-mediated dormancy in human cells: Inhibiting mTOR signaling in blastoids effectively induced a state of developmental delay, reducing growth and attachment capabilities. This finding suggests that mTOR activity could be a target to regulate embryo progression, with potential applications in managing implantation timing and understanding reproductive conditions related to early embryo development.

These results not only advance our understanding of human embryo implantation but also provide practical models and pathways that can be leveraged in reproductive health treatments. The blastoid model offers researchers a platform for high-throughput testing of drugs and genetic factors that could impact implantation. Furthermore, the insights into mTOR-mediated dormancy may inform the timing of implantation in IVF treatments, potentially improving outcomes. The research has been disseminated through publications and conferences.To share these outcomes, findings have been published in leading journals, ensuring accessibility to the wider scientific community.

Key publications include:

Generating human blastoids modeling blastocyst-stage embryos and implantation
Heidar Heidari Khoei, Alok Javali, Harunobu Kagawa, Theresa Maria Sommer, Giovanni Sestini, Laurent David, Jana Slovakova, Maria Novatchkova, Yvonne Scholte op Reimer & Nicolas Rivron, Nature Protocols, volume 18, pages 1584–1620 (2023)

mTOR activity paces human blastocyst stage developmental progression
Heidar Heidari Khoei, Dhanur P. Iyer, Vera A. van der Weijden, Harunobu Kagawa, Saurabh J. Pradhan, Maria Novatchkova, Afshan McCarthy, Teresa Rayon, Claire S. Simon, Ilona Dunkel, Sissy E. Wamaitha, Kay Elder, Phil Snell, Leila Christie, Edda G. Schulz, Kathy K. Niakan, Nicolas Rivron, and Aydan Bulut-Karslioglu, Cell

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

This project has advanced beyond current reproductive science through the successful generation of human blastoids from stem cells and modelling first steps of implantation, allowing precise modeling of the human blastocyst stage and implantation—a process previously challenging to observe due to ethical and technical barriers. This model captures the cellular complexity of natural blastocysts and has thus far provided valuable insights into early human embryo development. Moreover, the ability to delay developmental progression in blastoids through mTOR pathway inhibition is groundbreaking, as it reveals a regulatory mechanism for developmental pacing in human cells, previously seen in other species but unconfirmed in humans.

By the project’s conclusion, further refinement of the blastoid model is expected, enhancing its applications in high-throughput testing and screening for drugs and genetic factors affecting embryo implantation. Additionally, ongoing studies aim to further explore mTOR’s role and other molecular pathways that may govern blastocyst dormancy and implantation timing. These outcomes may set a foundation for new reproductive therapies and diagnostic tools, potentially leading to improved IVF outcomes and innovative contraception approaches.

The blastoid model's ability to test fertility treatments and optimize embryo implantation timing could significantly improve IVF success rates, reducing costs associated with multiple IVF cycles. By offering a scalable and ethical model for studying human implantation, this project could accelerate drug and gene therapy development for infertility, benefiting millions who experience reproductive challenges.

This research addresses a critical need for understanding human reproductive health, with implications extending to population health and family planning. Improved control over implantation timing could support family planning and contraception in new ways, potentially reducing unintended pregnancies. Furthermore, by expanding scientific understanding of early human development, this research fosters advancements in reproductive health policy, education, and accessibility, promoting broader societal awareness and health equity in reproductive care.

Human blastoid