Researchers develop functional eggs from human skin cells

Researchers at OHSU have demonstrated a new technique to treat infertility by turning skin cells into oocytes, or eggs. Shown here, an image of an oocyte with a bright image of a skin cell nucleus before fertilization.
Image Credit: Oregon Health & Science University

Researchers at Oregon Health & Science University have accomplished a unique proof of concept to treat infertility by turning skin cells into eggs capable of producing early human embryos.

The research published today in the journal Nature Communications.

The development offers a potential avenue for in vitro gametogenesis — the process of creating gametes — to treat infertility for women of advanced maternal age or those who are unable to produce viable eggs due to previous treatment of cancer or other causes.

“In addition to offering hope for millions of people with infertility due to lack of eggs or sperm, this method would allow for the possibility of same-sex couples to have a child genetically related to both partners,” said co-author Paula Amato, M.D., professor of obstetrics and gynecology in the OHSU School of Medicine.

Paula Amato, M.D. 
Photo Credit: Courtesy of OHSU

Researchers noted several limitations in their study, and that they expect at least a decade of further research before the approach could be deemed safe or effective enough to advance to a clinical trial, even assuming such a trial would be permitted in the United States.

Nonetheless, it represents a milestone in a promising technique to address infertility.

Shoukhrat Mitalipov, Ph.D.
Photo Credit: Courtesy of OHSU

“We achieved something that was thought to be impossible,” said senior author Shoukhrat Mitalipov, Ph.D., director of the OHSU Center for Embryonic Cell and Gene Therapy. “Nature gave us two methods of cell division, and we just developed a third.”

The researchers characterized their technique as “mitomeiosis,” alluding to the combination of the two major known processes of cell division in biology.

Mitosis generates two genetically identical cells from a single cell, the basis of cell growth in any living organism. Meiosis is strictly related to the sperm and egg cell in sexual reproduction, enabling the necessary halving the number of chromosomes in each so that the combination — in this case, through in vitro fertilization — results in an embryo with the correct number of chromosomes. In humans, that’s 23 pairs of chromosomes totaling 46.

In this case, researchers combined the two processes.

In vitro gametogenesis, or IVG, has become the focus of researchers across the globe working to address infertility among people who want to start a family with genetically related children.

Instead of attempting to reprogram induced pluripotent stem cells into sperm or egg cells — a process that can take months or even years — researchers at OHSU are using a technique based on somatic cell nuclear transfer. The technique involves transplanting a skin cell nucleus into a donor egg stripped of its nucleus. In 1997, researchers in Scotland famously reported this technique to clone a sheep named Dolly.

In that case, researchers created a clone of one parent.

In contrast, the OHSU technique resulted in embryos with chromosomes contributed from both parents. The process involved three steps:

• Researchers transplant the nucleus of a skin cell into an egg, or oocyte, stripped of its own nucleus.

• Prompted by cytoplasm within the donor egg, the implanted skin cell nucleus ideally discards half of its chromosomes in a process similar to meiosis. This is the key step, resulting in a haploid egg with a single set of 23 chromosomes rather than 46.

• Researchers then fertilized the new egg with sperm through the standard process of IVF. This created a diploid embryo with two sets of chromosomes — which would ultimately result in healthy offspring with equal genetic contributions from both parents.

Researchers reported that they had produced 82 functional oocytes that were then fertilized with sperm through IVF.

Notably, most did not progress beyond the 4- to 8-cell stage and displayed chromosomal abnormalities.

A relatively small number — 9% — developed to the blastocyst stage of development six days after fertilization, when embryos are typically transferred to establish a pregnancy through IVF. None were cultured beyond that point.

Nuria Marti-Gutierrez, Ph.D.
Photo Credit: Courtesy of OHSU

First author Nuria Marti Gutierrez, Ph.D., staff scientist in the OHSU Center for Embryonic and Cell Therapy, said research will continue to better understand how chromosomes pair and separate faithfully to create oocytes with the correct number of chromosomes. Embryos typically won’t develop if they have too many or too few chromosomes, a condition known as aneuploidy.

Mitalipov noted that even in natural reproduction, only about a third of embryos develop to blastocysts.

“Aneuploidy is pretty common in human eggs, especially with aging,” he said.

Researchers noted that the publication represents a scientific milestone, but that much remains to be done before the technique would be ready to establish a pregnancy in people.

“While our study demonstrates the potential of mitomeiosis for in vitro gametogenesis, at this stage it remains just a proof of concept and further research is required to ensure efficacy and safety before future clinical applications,” the authors write.

Funding: The research was supported by funding from Open Philanthropy, the Haploid Gamete Research Foundation and OHSU institutional funds. The project also was supported by a Longevity Impetus Grant from Norn Group, Hevolution Foundation and Rosenkranz Foundation.

Additional information: Research adhered to guidelines and oversight from OHSU’s Institutional Review Board as well as a Data Safety Monitoring Committee that reviewed all gamete and tissue donations, the use of samples and any adverse events among study participants. 

Published in journal: Nature Communications

Title: Induction of experimental cell division to generate cells with reduced chromosome ploidy

Authors: Nuria Marti Gutierrez, Aleksei Mikhalchenko, Maria Shishimorova, Daniel Frana, Crystal Van Dyken, Ying Li, Hong Ma, Amy Koski, Dan Liang, Sang-Goo Lee, Daniel Eyberg, Zahra Safaei, Eunju Kang, Yeonmi Lee, Thomas O’Leary, David Lee, Sacha Krieg, Diana Wu, Elizabeth Rubin, Paula Amato, and Shoukhrat Mitalipov

Source/Credit: Oregon Health & Science University | Erik Robinson

Reference Number: bio093025_02

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