Sperm Made (Mostly) in a Dish Produce Normal Mice

Scientists have long wanted to produce sperm and eggs in the laboratory to not only better understand this fundamental reproductive process but also to discover new ways of helping infertile couples conceive. Using embryonic stem (ES) cells, which in theory can produce all of the body's cell types, several teams made some progress in the past few years but were unable to produce viable sperm or eggs. Now a Kyoto University group has found a way to turn mouse ES cells into sperm precursor cells and to use the resulting sperm to produce normal mouse pups. Such research may eventually lead to treatments for human male infertility. But that will require resolving several "very difficult" technical and ethical issues, says stem cell biologist Mitinori Saitou, leader of the Kyoto team.

Sperm and eggs develop from what are known as primordial germ cells. These germ cells are produced in early stage embryos in a mass of cells called the epiblast. Several years ago, researchers learned how to take epiblast cells from a mouse embryo and create epiblast stem cells that could regenerate in a dish for long periods of time. Researchers hoped that these epiblast stem cells could be used to produce primordial germ cells and ultimately fertile sperm and eggs. But despite years of attempts, no one succeeded. The Kyoto group concluded that when the lab-created epiblast stem cells gained their ability to grow in dishes, they may have lost their ability to form germ cells.

So taking a different approach, the scientists cultured mouse ES cells in cocktails of growth factors and proteins to produce epliblast-like cells that they could keep alive only for several days. They found that they could use 2-day-old cells to generate primordial germ cell-like cells. When injected into the testes of mice unable to produce their own sperm, these primordial germ cells matured into sperm that were able to fertilize eggs in vitro. The researchers implanted the resulting embryos into surrogate mothers, which produced normal offspring. Those mice then produced their own offspring. Saitou and his colleagues report their work online today in Cell.

"All I can say is wow! It is a breakthrough," says Orly Lacham-Kaplan, a reproductive biologist at Monash University in Australia. The work provides evidence "that ES cell-derived primordial germ cells can generate functional germ cells," says Amander Clark, a stem cell biologist at University of California, Los Angeles, who calls the work "a critical advance to our basic understanding of the principles of germ cell development."

Saitou says that there are many hurdles to clear. They would like to learn how to develop sperm completely in the laboratory instead of injecting primordial germ cell-like cells into the testes for maturation. They also want to generate eggs in vitro, both to understand the process and to ultimately try to help infertile women. Saitou also says that extending the work to the clinic will require determining if the same recipe they figured out for mouse cells works for human cells as well.

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