A group of researchers at Penn and other universities has identified a receptor that plays a key role in restricting embryonic stem cells’ pluripotency—the ability to develop into virtually any one of an adult animal’s many kinds of cells. By repressing that mechanism, it may be possible to find new ways of creating embryonic stem cells without using embryos, says Dr. Hans Scholer, the Marion Dilley and David George Jones Chair in Reproduction Medicine and associate professor of reproductive physiology at Penn’s School of Veterinary Medicine.
Although Scholer and his colleagues were using mouse embryos for their experiments, the implications of their discovery are considerable, given the ethical, political, and practical issues involved in using human embryos. (Last August, President George W. Bush announced that federally funded research would be limited to those stem-cell lines already harvested from frozen embryos, prompting many researchers to seek alternative sources.)
The receptor, known as GCNF (for Germ Cell Nuclear Factor), is the first factor known to repress the Oct4 gene, which is expressed in pluripotent embryonic cells.
“In a sense, we’re hoping that understanding what GCNF actually does as it shuts down genes will let us turn back the clock on cellular development,” said Scholer, who also serves as director of the school’s Center for Animal Transgenesis and Germ Cell Research. “This knowledge may permit us to convert ordinary adult cells back to embryonic stem cells for research purposes.” An article detailing the results of Scholer’s work appeared in the September issue of the journal Developmental Cell. His Penn colleagues were Dr. Guy Fuhrmann and Dr. Ian Sylvester.
Though there “very likely” are other factors besides GCNF that can repress Oct4, Scholer says, “if you take away one, it’s like taking a can from the bottom of a pile in a supermarket—efficient repression collapses.” And so far, the Oct4 gene is the only one known to play an essential role in maintaining pluripotency. When its expression is repressed, pluripotency is lost.
“The question was: how does the embryo switch Oct4 off?” notes Scholer, who has been probing the secrets of that gene for several years. He and his colleagues focused on the time when the embryo is “gastrulating”—when the body is starting to be formed from embryonic stem cells: between the sixth and seventh days after conception in mice. That is when an embryonal stem cell, according to its “positional information” (the location within the embryo), starts to differentiate instead of renewing itself. And by comparing the Oct4 genes from human, bovine, and mouse, Scholer adds, they learned “which areas of the gene are required for down-regulating the Oct4 gene.”
“The repressors probably come, set a [chemical] mark, and then leave,” says Scholer, who came to Penn in 1999 from the University of Heidelberg, where he headed a research group in the European Molecular Biology Laboratory. Asked what his next step is, he replies: “We think we know which mark is set by GCNF, and will now try to remove it chemically.” And if they’re successful, he adds, “we will try to clone the cellular molecules.”
