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Source: Wallace Ravven
415-476-2557
14 June 2001
Gene that directs fate of many embryonic stem cells identified
Scientists have identified the gene that prompts embryonic stem cells to generate precursors to most internal organs. The finding suggests a potent new way of coaxing stem cells to produce high numbers of specialized cells that can form medically needed tissues such as insulin-producing pancreatic cells, the scientists say.
The research led by University of California, San Francisco scientists is based on studies of zebrafish, an animal that has become a powerful model of early human embryo development. Strong evidence indicates that the pivotal gene plays the same role in humans as it does in zebrafish: inducing embryonic stem cells to produce endoderm, the source material for many specialized cells and tissues, including the pancreas, liver, thymus and thyroid.
"Exploiting this master gene, we can control stem cell differentiation from the inside, as opposed to trying to boost differentiation from the outside with growth factors," said Didier Stainier, PhD, UCSF associate professor of biochemistry and biophysics and senior author on a paper reporting the research.
The study is published in the June 15 issue of Genes and Development.
Embryonic stem cells are the focus of intense research interest because their ability to give rise to all tissues of the body make them a potentially vital player in regenerative medicine. The researchers dubbed the master gene they isolated casanova because mutant animals lacking the gene have a split heart. Casanova or cas, the team found, is essential and sufficient to prod embryonic stem cells into making endodermal cells. These, in turn, give rise to many internal organs, as well as the lining of the lungs and gut.
Ambitious new efforts to restore the insulin-producing capacity in people with type 1 diabetes rely on injections of insulin-producing beta cells. But the supply of these cells is severely limited. Endoderm gives rise to these beta cells, and also to the liver's hepatocytes. By harnessing casanova's potent effect, researchers would have a certain way to boost the supply of these vital cells needed to cure rather than treat Type 1 diabetes and various forms of liver disease, Stainier said.
"If you can gain access to the earliest stages of cell specialization through the genes that directly control the process from within the cell," Stainier says, "you have a much more powerful tool to generate desired cells than if you simply try to increase the numbers of needed cells after they have specialized," he concluded.
In the last two years, the UCSF team isolated two other genes central to embryonic stem cell fate, named faust and bonnie and clyde. Like the first two, casanova codes for a protein that directly controls gene expression in the nucleus. Known as transcription factors, these proteins contact selected genes and turn them on in response to some other signal. Casanova, the scientists found, is the most potent director of stem cell fate into endoderm. It is the "central regulator" of endoderm formation, they conclude.
In experiments that sound philosophical as well as biological, the researchers demonstrated that they could change the fate of early embryonic cells by lacing them with the cas gene. They first showed that mutant zebrafish lacking the casanova gene failed to develop endoderm at all. In a second round of experiments, embryonic stem cells that normally develop into mesoderm -- source material for the heart, kidney and muscles in all organisms -- were "transfated" into endoderm - the source for an entirely different set of tissues. When just-fertilized embryos were injected with the cas gene, 100 percent of the embryonic stem cells that normally form mesoderm instead gave rise to endoderm.
"The complete transformation of embryonic cell fate under the influence of the casanova gene's product, combined with the mutant experiments, demonstrate that this gene is the central regulator of embryonic stem cell development into endoderm," Stainier said. "This gene appears to be a potent candidate to improve the efficiency of directing embryonic stem cells to produce medically needed cells and tissues."
"Our next step is to demonstrate that the human casanova gene has the same properties as the zebrafish gene." Stainier said he fully expects this is the case.
Lead authors on the paper are Yutaka Kikuchi, PhD, a postdoctoral scientist in Stainier's lab, and Antoine Agathon, a graduate student at the Institut de Genetique et Biologie Moleculaire et Cellualaire in Strasbourg, France. Co-authors and collaborators in the research are Deborah Yelon, PhD, a postdoctoral scientist; Jonathan Alexander, graduate student, and Steven Waldron, research associate, all in Stainier's lab; and Christine and Bernard Thisse, directors of research at the Institute in Strasbourg.
The research was funded by the National Institute of Health and the Packard Foundation.
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