PHILADELPHIA – Scientists at the University of Pennsylvania have identified a receptor that plays a key role in restricting embryonic stem cells’ pluripotency, their ability to develop into virtually any of an adult animal’s cell types. The work is the first demonstration of a mechanism by which pluripotency is lost in mammalian embryos, one that operates with nearly the precision of an on/off switch in mouse embryos.
With further study, the receptor, dubbed GCNF, could open the door to new ways of creating embryonic stem cells without the ethical concerns associated with sacrificing embryos. GCNF, short for germ cell nuclear factor, was detailed in a recent paper in the journal Developmental Cell.
"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 senior author Hans R. Schöler, professor of animal biology at Penn’s School of Veterinary Medicine. "This knowledge may permit us to convert ordinary adult cells back to embryonic stem cells for research purposes."
Schöler, also the director of Penn’s Center for Animal Transgenesis and Germ Cell Research, said GCNF is the first factor known to repress the key gene Oct4, which is expressed in pluripotent embryonic cells. While GCNF is likely just one cog in a complex cellular machinery that dictates pluripotency among the cells of mouse embryos, Schöler’s team believes it is a crucial player: without GCNF, restriction of pluripotency does not occur properly and the embryo eventually dies.
"The identification of GCNF as a repressor of Oct4 expression opens up several new avenues for understanding Oct4 regulation and, therefore, the control of the pluripotent state," wrote Peter J. Donovan of Thomas Jefferson University in an analysis appearing in the November issue of Nature Genetics. "The identification of a nexus between Oct4 and GCNF provides some critical clues as to how the differences between pluripotent and differentiated cells are established and maintained."
Active in a very limited population of cells, Oct4 is the only gene known to play an essential role in maintaining pluripotency. Whenever its expression is suppressed, as by GCNF, pluripotency is lost. Oct4’s tightly regulated activity decreases steadily as embryonic stem cells differentiate; GCNF eventually restricts Oct4’s expression in the body’s somatic cells, leaving expression only in the germ cell lineage.
With President Bush’s August declaration that federally funded research would be limited to stem cell lines already harvested from frozen embryos, many researchers are looking to alternative sources. Embryonic stem cells’ scientific appeal lies in their pluripotency: they have not yet determined their ultimate role, so each has the potential to become one of more than 200 tissue types in the body.
Scientists can now isolate stems cells, induce them to multiply and preferentially direct them to become, for example, skin cells, nerve cells or heart cells. This opens the door to replacing damaged adult cells that are not able to regenerate and may ultimately allow scientists to grow replacement organs for those in need of a new heart, lung or liver.
Schöler was joined in the September Developmental Cell paper by Guy Fuhrmann and Ian Sylvester of Penn; Arthur C.-K. Chung, Kathy J. Jackson, Geoffrey Hummelke and Austen J. Cooney of Baylor College of Medicine; Aria Baniahmad of the University of Giessen in Germany; and Julien Sutter of the Centre du Neurochimie in Strasbourg, France. Their work was funded by the National Institutes of Health, the Marion Dilley and David George Jones Funds and the Commonwealth and General Assembly of Pennsylvania.
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