It is the first atlas of the human ovary with such resolution that it can 'see' down to the cell level. And the scientists who created it consider it an important step forward towards one day reaching the goal of creating artificial ovaries in the laboratory that could eventually be transplanted. The undertaking bears the signature of a group of bioengineers from the University of Michigan. The new “atlas” offers insights that could lead, for example, to identifying strategies to restore ovarian hormone production and the ability to have children.
Potentially, experts explain, with the information that can be accessed from this ultra-detailed 'catalogue', researchers could create artificial ovaries in the laboratory using tissues that have been preserved and frozen before exposure to toxic medical treatments such as chemotherapy and radiation. Currently, surgeons can implant previously frozen ovarian tissue to temporarily restore hormone and egg production. However, it doesn't work for long because few follicles – the structures that produce hormones and transport eggs – survive reimplantation. The atlas reveals the factors that allow a follicle to mature and explains why most wither without releasing hormones or an egg.
Using new tools that can identify which genes are expressed at the single-cell level within a tissue, the team was able to identify the ovarian follicles that carry the immature precursors of eggs, i.e. oocytes. “Now that we know which genes are expressed in oocytes – explains Ariella Shikanov, associate professor of biomedical engineering at the University of Michigan and corresponding author of the new study published in 'Science Advances' – we can test whether the influence of these genes can lead to creation of a functional follicle, which could be used to create an artificial ovary for eventual transplantation.”
Most follicles, called primordial follicles, remain dormant and are found in the outer layer of the ovary, called the cortex, the authors illustrate. A small portion of these become periodically activated and migrate into the ovary, in a region known as the growth pool. And only a few of these growing follicles produce mature eggs that are released into the fallopian tubes. By guiding follicle development and regulating the ovarian environment, the team believes that the engineered ovarian tissue could function much longer than unmodified implanted tissue. This means patients would have a longer fertility window and a longer period in which their bodies produce hormones that help regulate the menstrual cycle and support muscular, skeletal, sexual and cardiovascular health.
“We're not talking about using a surrogate mother or artificial insemination,” points out Jun Z. Li, Department of Computational Medicine and Bioinformatics at the University of Michigan and co-corresponding author of the study. “The magic we are working on is to be able to bring an immature cell to maturity, but without knowing which molecules drive that process we are blind.” The team used a relatively new technology, called spatial transcriptomics, to track all the genetic activity and where it occurs in the tissue samples. It is done by reading the RNA strands, which are like notes taken from the DNA strand, and reveal which genes are being read. Then the researchers performed RNA sequencing of the ovaries of 5 human donors.
“It was the first time we could point the lens at ovarian follicles and eggs and perform an analysis that allows us to see which genes are active,” adds Shikanov. “Most ovarian follicles, already present at birth, never enter the growth pool and eventually self-destruct. This new data allows us to begin to understand what makes a good egg, what determines which follicle will grow, ovulate, come fertilized and will become a child.” The work of the US university is part of the 'Human Cell Atlas' project, which aims to create “maps of all the different cells, their molecular characteristics and where they are located, to understand how the human body works and what goes wrong if of illness”. Shikanov, Li and colleagues are mapping other parts of the female reproductive system, including the uterus, fallopian tubes and ovaries. The research in question was partially funded by the Chan Zuckerberg Initiative. Additional financial support was provided by the National Institutes of Health.
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