Researchers at Brown University have created an "artificial human ovary" using a tissue engineering approach that they hope will one day allow scientists to mature human eggs in a laboratory.
In the near term, an artificial ovary will enable researchers to better explore the impact of environmental toxins or fertility-enhancing substances on human fertility. It could also aid the development of new forms of contraceptives and the study of ovarian cancer.
Reproductive research: This artificial human ovary surrounds granulosa cell spheres, which are marked with fluorescent green dye.
Further down the line, it could also help women whose ovaries are damaged because of chemotherapy, radiation, or illness, according to a paper published in the current issue of Journal of Assisted Reproduction and Genetics. Today, those women have limited opportunities for childbirth: either a hurried in-vitro fertilization cycle that leads to a handful of frozen eggs, or freezing ovarian tissue in the hopes that healthy eggs will someday be able to be matured.
An artificial ovary, where immature eggs could be harvested by the thousands and then matured at will in the laboratory, would open up huge possibilities for the one in a 1,000 women who need it, says the paper's first author, Stephan Krotz, who was a graduate student at Brown when he worked on the paper.
The artificial ovary marks the first time researchers have successfully created a three-dimensional environment that contains the three main types of ovarian cells: theca cells, granulosa cells, and the eggs, known as oocytes. The paper's lead researcher is Sandra Carson, a professor of obstetrics and gynecology at Brown and Woman and Infants Hospital of Rhode Island.
Alan B. Copperman, director of infertility at Mt. Sinai Medical Center in New York, says clinical benefits are years and many scientific hurdles away, but he's impressed by the research potential of the group's work. "The concept of creating an artificial three-dimensional environment, and the fact that we can take out immature eggs and let them grow and mature into viable eggs, is really exciting," he says.
Copperman says the artificial ovary could serve as a model to help researchers better understand the ovarian aging process, the focus of much of his research. "If we can establish a viable testing environment, we can learn more about how to optimize eggs, and discriminate good from bad eggs."
The Brown researchers' innovation was using a honeycomb-shaped mold to support the egg. Human eggs are too large to be grown without some kind of support structure. "If you try to grow it by itself, in a dish, it basically collapses on itself," says Krotz, now a reproductive endocrinologist and fertility specialist at the Advanced Fertility Center of Texas.
The researchers broke ovarian cells out of human tissue using enzymes, and poured them into a mold made of agar, a gelatinous substance usually derived from algae. The different types of cells then assembled themselves into a honeycomb shape, with the theca and granulosa cells forming the structure. The egg cells, or oocytes, were inserted inside and bathed with hormones to stimulate the theca cells to produce androgen, and the granulosa cells to make estrogen.
"We took a different tack to rely on the inherent adhesiveness of cells to drive self-assembly," says Jeffrey Morgan, codirector of the Center for Biomedical Engineering at Brown, who led this aspect of the research. "In that nonadhesive environment, the cells will stick to each other and self-assemble a three-dimensional structure, and it conforms to the shape of our mold."
Researchers had assumed that, if allowed to self-assemble, cells would form a sphere, but Morgan says he showed that they can also create more complex forms with a little prompting.
Kim L. Thornton, a reproductive endocrinologist at Boston IVF, one of the nation's largest fertility centers, says it's tricky to re-create in a lab all of the activities that go on in a woman's ovaries. "One of the challenges with maturation is, there are lot of things that go on locally that may affect the ability of oocytes to become mature," she says. "We can't duplicate all of those conditions" in a lab dish. However, Thornton says, the Brown model "is interesting, and it's certainly promising."
Carson says that now that the team has created the model, she wants to go back and look more closely at how it functions. She would like to identify various proteins involved in egg maturation, and be able to explore whether those proteins can be altered as a means of contraception. "We could also theoretically find something that might be important in the development of ovarian cancer," she says.
The work can also be used to test for toxic effects from everyday products, such as plastics and insecticides, as well as medications--"anything we might be able to test against the control," Carson says. "We're not there yet, but I think this is going to be the most powerful use of the model."
By Karen Weintraub
From Technology Review