A recent discovery of a human ovary “atlas” by University of Michigan engineers sheds light on potential treatments for restoring ovarian hormone production and the ability to conceive biologically related children. This newfound knowledge of the ovary could pave the way for the development of artificial ovaries in the laboratory using previously frozen tissues.According to the researchers, traditional cancer treatments like chemotherapy and radiation can harm the ovaries. In an attempt to restore hormone and egg production, surgeons have been able to implant frozen ovarian tissue. However, this method is not very effective in the long term because very few follicles, which are responsible for producing hormones and carrying eggs, actually survive the reimplantation process. The new atlas created by the research team has identified the factors that allow a follicle to mature, as many follicles typically die off without releasing hormones or an egg. The team utilized new tools to pinpoint the genes being expressed at a single-cell level within the ovarian tissue.follicles contain immature precursors of eggs, known as oocytes. “Now that we have identified the genes expressed in the oocytes, we can investigate whether manipulating these genes could lead to the creation of a functional follicle. This could be used to develop an artificial ovary that may be transplanted back into the body,” said Ariella Shikanov, U-M associate professor of biomedical engineering and author of the new study in Science Advances. The majority of the follicles, known as primordial follicles, remain inactive and are found in the outer layer of the ovary, known as the cortex. Only a small portion of these follicles contain immature egg precursors.Follicles activate periodically and move into the ovary, to an area called the growing pool. Only a small number of these growing follicles proceed to create fully developed eggs that are released into the fallopian tube.
The team believes that by being able to control follicle development and adjust the ovarian environment, engineered ovarian tissue could potentially function for a much longer period of time compared to unmodified implanted tissue. This would mean that patients could have an extended fertility window and a longer duration during which their bodies produce hormones that help regulate the menstrual cycle and support overall health, including muscular, skeletal, sexual, and cardiovascular health.
“WeJun Z. Li, associate chair of U-M’s Department of Computational Medicine and Bioinformatics and co-corresponding author of the study, explained that the research is not about using a surrogate mother or artificial insemination. The goal is to trigger an immature cell into maturity without knowing which molecules drive that process, which presents a challenge.
The team at U-M used spatial transcriptomics, a relatively new technology, to track all gene activity and its location in tissue samples. This is done by reading RNA strands, which are similar to notes taken from the DNA strand, to reveal the molecules involved in the process.
Researchers at the University of Michigan worked with an organ procurement organization to conduct RNA sequencing on ovaries from five human donors. This allowed them to analyze which genes are active in ovarian follicles and oocytes for the first time.
Dr. Shikanov explained, “This was the first time where we could target ovarian follicles and oocytes and perform a transcription analysis, which enables us to see which genes are active.”
He also mentioned, “The majority of ovarian follicles, already present at birth, never enter the growing pool and eventually self-destruct. 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.”
U-M’s research is part of the Human Cell Atlas project, which aims to create maps of all the different cells, their molecular characteristics, and their locations. The goal is to understand how the human body works and what causes disease.
Shikanov, Li, and other U-M collaborators, such as Sue Hammoud, are also mapping other parts of the female reproductive system, such as the uterus, fallopian tubes, and ovaries. Additional contributors to the project include Andrea Suzanne Kuliahsa Jones, who was previously at U-M and is now at Duke University, and D. Ford Hannum, a U-M graduate student researcher.
The study was supported in part by the Chan Zuckerberg Initiative and received additional funding from the National Institutes of Health.
