Most human oocytes never get a chance to mature into eggs—a new study sheds light on why

A new ‘atlas’ of the human ovary provides insights into how healthy eggs develop and hormones are produced. It could lead to new research to restore ovarian endocrine function and the ability to have biologically related children, according to University of Michigan researchers.

Using new genetic tools, U-M’s team was able to measure the activity of most genes in many locations in the ovary—particularly around the follicles, which produce hormones and carry the precursors of eggs, called oocytes. The work revealed the factors that enable oocytes to mature into healthy eggs.

“Now that we discovered dozens of new genes that are specifically expressed in the oocytes and supporting cells, we can test whether affecting these genes could result in creating a functional follicle,” said Ariella Shikanov, associate professor of biomedical engineering, who co-led the study in Science Advances with Jun Li, professor of human genetics.

This new map of the ovary provides a deeper understanding of how oocytes mature. During reproductive years, the majority of the follicles remain dormant in the ovary’s outer layer. Every month, a small portion of these follicles activate and migrate deeper into the ovary where they gradually mature. Only a few of them eventually produce eggs that get released into the fallopian tube, and the study reveals factors that distinguish those few.

“This new data allows us to start building our understanding of what makes a good egg—what determines which follicle is going to grow, ovulate, be fertilized and become a baby,” Shikanov said.

It also sheds light on how follicles stop working in aging or fertility related diseases. Such knowledge may accelerate the development of artificial ovaries.

Currently, surgeons can implant previously frozen ovarian tissue—stored before exposure to toxic medical treatments such as chemotherapy and radiation for cancers—to temporarily restore hormone production and egg maturation. However, this does not work for long because so few follicles survive through reimplantation, the researchers say.

To discover the location and function of the key cells involved in maturing the oocyte, the team used a new genetic tool called spatial transcriptomics. This technique allowed researchers to read strands of RNA, which are like notes taken from the DNA strand, revealing which genes are being activated with nearly cell-level resolution. Working with an organ procurement organization, the team mapped the ovaries of five young donors without prior disease in the ovary.

“When analyzing single cells, we don’t know where they were in the tissue. With spatial analyses we can focus on cells in the most important locations,” Li said. “This is especially helpful in the ovary, where the oocytes and supporting cells are very rare when compared to other cell populations.”

With the ability to control the environment around follicles and guide their development, the team believes that engineered ovarian tissue could function for much longer than unmodified tissue. This means patients would have a longer fertility window as well as a longer period in which their bodies produce hormones that help regulate the menstrual cycle and support the health of other organs, such as the heart, breasts and bone.

The team’s ability to analyze the data that tracked all of the gene activity was supported by funding from the Chan Zuckerberg Initiative. U-M researchers are part of the initiative’s Female Reproductive System Seed Networks. Additional financial support was provided by the National Institutes of Health.

The study is part of the Human Cell Atlas project, which seeks to “map every cell type in the human body to transform understanding of health and disease.” The new spatial technology adopted by the team, NanoString GeoMx, was established in U-M by the Single-Cell Spatial Analysis Program, part of the Biosciences Initiative.

The majority of the study was carried out by the two co-first authors: Andrea S.K. Jones, who recently graduated from U-M with a Ph.D. in biomedical engineering, and D. Ford Hannum, Ph.D. student of bioinformatics at U-M. Sue Hammoud, associate professor of human genetics, and Erica Marsh, professor of obstetrics and gynecology, are also principal investigators of U-M’s Seed Network and study co-authors.