Scientists transform skin cells into functional eggs in mice

New research from Oregon Health & Science University describes the science behind a promising technique to treat infertility by turning a skin cell into an egg that is capable of producing viable embryos.

OHSU researchers have documented in vitro gametogenesis, or IVG, in a mouse model through the preliminary steps of a technique that relies on transferring the nucleus of a skin cell into a donor egg whose nucleus has been removed. Experimenting with mice, the researchers forced the nucleus of a skin cell to halve its chromosomes so that it could then be fertilized by sperm to create a viable embryo.

The study, published today in the journal Scientific progress.

“The goal is to produce eggs for patients who do not have their own eggs,” said the senior author Shuhrat Mitalipov, Ph.D., director of the OHSU Center for Embryonic Cell and Gene Therapy.

The technique can be used by women of advanced maternal age or those who cannot produce viable eggs due to previous cancer treatment or other reasons. It also raises the possibility that men in same-sex relationships will have children who are genetically related to both parents.

Instead of trying to differentiate induced pluripotent stem cells, or iPSCs, into sperm or eggs, the OHSU researchers focused on a technique based on somatic cell nuclear transfer, in which the nucleus of a skin cell is transplanted into a donor egg cell stripped of its nucleus. In 1996, researchers used this technique to clone a sheep in Scotland named Dolly.

In this case, the researchers created a clone of one parent.

In contrast, the OHSU study describes the result of a technique that results in embryos with chromosomes contributed by both parents. The process involves three steps:

• The researchers transplanted the nucleus of a mouse skin cell into a mouse egg that had been deprived of its own nucleus.
• Suggested by the cytoplasm -; fluid that fills the cells -; within the donor egg, the implanted skin cell nucleus sheds half of its chromosomes. The process is similar to meiosis, where cells divide to produce mature sperm or eggs. This is the key step that results in a haploid egg with one set of chromosomes.
• Researchers then fertilize the new egg with sperm, a process called in vitro fertilization. This creates a diploid embryo with two sets of chromosomes -; which would eventually result in healthy offspring with equal genetic contributions from both parents.

OHSU researchers previously demonstrated the proof of concept in a study published in January 2022, but the new study goes further by meticulously sequencing the chromosomes.

The researchers found that the nucleus of the skin cell shed its chromosomes each time it implanted into the donor egg. In rare cases, this happens perfectly, with one of each pair of matching chromosomes from egg and sperm.

“This paper basically shows how we achieved haploidy,” Mitalipov said. “In the next phase of this research, we will determine how to improve this pairing so that each chromosome pair separates correctly.”

Laboratories around the world are involved in a different IVG technique, which involves a time-intensive process of reprogramming skin cells to become iPSCs and then differentiating them to become eggs or sperm.

We skip this whole step of reprogramming the cell. The advantage of our technique is that it avoids the long culture time required for cell reprogramming. Over the course of a few months, many deleterious genetic and epigenetic changes can occur.”

Paula Amato, Professor of Obstetrics and Gynecology, School of Medicine, Oregon Health & Science University

Although researchers are also studying the technique in human eggs and early embryos, Amato said it will be years before the technique is ready for clinical use.

“It gives us a lot of insight,” she said. “But there’s still a lot of work to be done to understand how these chromosomes pair up and how they faithfully separate to actually replicate what happens in nature.”