Oogenesis spotlighted: making mature human oocytes

Project Information

OVO-GROWTH

Grant agreement ID: 725722

DOI

10.3030/725722

Project closed

EC signature date 16 June 2017

Start date 1 July 2017

End date 28 February 2023

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 2 000 000,00

EU contribution

€ 2 000 000,00

Coordinated by

ACADEMISCH ZIEKENHUIS LEIDEN
Netherlands

Periodic Reporting for period 4 - OVO-GROWTH (Oogenesis spotlighted: making mature human oocytes)

Reporting period: 2022-01-01 to 2023-02-28

Summary of the context and overall objectives of the project

Women who survive childhood cancer often fail to conceive because their eggs are damaged by (gonadotoxic) chemotherapy. A major breakthrough has been the possibility to cryopreserve cortical strips of their ovarian tissue for autologous transplantation later in life. This has led to hundreds successful pregnancies worldwide, several in the Netherlands. However, the risk of reintroducing cancer cells with the ovarian graft in patients with previous hematopoietic malignancies is too great and alternatives are needed.

Our overall objective was to understand the process that leads to egg maturation in humans and achieve maturation of human eggs in vitro.

During the project, we have first provided a comprehensive analysis of the key cellular components, developmental networks and molecular signalling in the human ovary during development and adulthood. We have characterized both follicular growth and follicular degeneration (atresia) and focused not only on the oocyte biology and also on the dynamics of the surrounding cellular niche. We have investigated the role of the immune system and vasculature. Thereafter, we have invested in innovative culture methods to promote the egg maturation in vitro.

In conclusion, this challenging and ambitious project has led to a robust foundation to allow progress in innovative protocols to increase options regarding female health management and reproduction.

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

During the project, we have performed a detailed analysis of the cellular composition and molecular signature that control development and maturation of the egg cell within the human ovary from fetal and adult tissue using single-cell transcriptomics. Moreover, we have used adult ovary tissue to develop a culture method to grow primordial follicles from cryopreserved ovarian cortex using different culture media and scaffolds. We have worked on culture protocols not only to use on fresh ovarian tissue, but to use on cryopreserved ovarian tissue from cisgender and transgender persons. Finally, using fetal ovaries we have been investigating the origin of granulosa cells, the somatic cells that support the egg cell during maturation, using live imaging and electron microscopy.

Our work has the potential to refine and transform fertility preservation options, impacting the quality of life of a growing number of people that include oncological patients and transgender man. As international recognition, I was invited to deliver the Anne McLaren Memorial Lecture at the annual meeting of the International Society for Stem Cell Research (ISSCR) in 2021.

Due to extensive knowhow acquired during this project, I was invited to join the EU-expert taskforce to create an evidence-based guideline from the European Society of Human Reproduction and Embryology (ESHRE) on Female Fertility Preservation, and I was invited to join the EU-expert taskforce advising on the Reproductive and Development Systems to the European Space Agency (ESA) SciSpacE roadmap, providing me with a larger international platform to disseminate the work developed during the project.

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)

The most important protocol that has been developed during the project is a robust foundation to allow follicular growth and maturation from cryopreserved ovarian cortex in vitro, as this will impact tremendously the way fertility preservation is offered currently.

Having the research protocol translated into a suitable clinic protocol would enlarge the group of patients that could benefit from fertility preservation, avoiding a surgical procedure (transplantation of cryopreserved ovarian cortex into the patient) and allow innovation in medical assisted reproduction as ovarian hormonal stimulation would no longer be necessary prior to oocyte pick up.

In addition to a more effective personalized-therapy for fertility preservation, the project has contributed to develop an in vitro mini-ovary organoid model that can be applied to human reproductive toxicology and disease modelling.

he-ovary-follicles.jpg

Fetal ovary showing germ cells (cyan) in different phases of meiosis, expressing H2AX and SCML1