Sep. 13, 2002 Princeton University scientists have taken a major step toward identifying the "genetic signature" of stem cells, discovering a subset of genes whose products may give these cells their unique traits. The results promise to become an important resource to biologists as well as medical researchers who are trying to harness stem cells as therapies for neurological diseases, birth defects, heart disease, blood cancers and many other disorders.
In two papers published this week, Princeton biologists identified 283 genes that are common to several of the most important types of stem cells, as well as about 4,000 genes that are active in the surrounding tissues that nurture stem cells and give them cues about how to behave. Databases of these genes have been published online and are freely available to anyone.
"The question we have been asking is: Can we identify the molecular parts list, or toolbox, that the stem cell has at its disposal?" said Ihor Lemischka, the senior author of one of the papers. "We found that there is a core set of molecular machinery that might be responsible for regulating the activities that make stem cells unique."
Currently scientists identify stem cells by the way they behave and by chemical markers on the cell surface. However, the genes that give rise to these characteristics remained largely unknown. A comprehensive catalog of stem cell genes could refine the identification process, as well as reveal the mechanisms that make the cells function as they do.
In one paper, published in the Sept. 12 online edition of Science, a group led by Lemischka looked at several kinds of stem cells, including embryonic stem cells and those of the blood and nervous systems, and identified a core set of genes that were common to all of them. They also compared mouse and human blood stem cells and noted a core gene set common to stem cells of both species.
"We wanted to know if there is such a thing as a generic stem cell molecular signature," said Lemischka. "In large part, we think there is, and that is what this paper shows."
The other paper, published Sept. 11 in the online edition of the Proceedings of the National Academy of Sciences, focused on the cells surrounding stem cells, known as the stem cell microenvironment. Previously, the researchers, led by Princeton biologist Kateri Moore, looked at more than 200 cell lines derived from mouse fetal livers and found one that was particularly effective supporting stem cells.
In the current paper, Moore's research team, which included scientists from the University of Pennsylvania and France, compared the genes active in the supportive cells to those in cells that did not support stem cells. They documented the activity of more than 4,000 genes in the stem cell supportive cells, but not in the others. Not all those genes are necessarily critical for supporting stem cells, but any that are required are almost certainly part of that group, said Moore.
"It was my feeling we just didn't know enough about these supportive cells," said Moore. "We needed to know a lot more about the basic biology." Such knowledge will be crucial in making widespread use of stem cells in medicine, she said.
Stem cells are master cells that serve as progenitors of the many kinds of tissue in the body. The most potent of these are embryonic stem cells, which are precursors of every tissue, from bones to nerves. Blood stem cells are more specialized, but still are a wellspring; a single one can spawn all the red and white blood cells, platelets and other constituents of blood.
The hallmark of all stem cells is that, as they multiply, they strike a balance between replenishing their own numbers and spawning mature cells dedicated to specific tasks. The cues that determine whether a stem cell replaces itself or produces a more specialized offspring come from both within and from outside of the cell, said Lemischka.
"That is why we think these papers are so complementary," he said. "They form the Princeton group's philosophy for how to proceed in stem cell biology. You have to do it simultaneously from the point of view of the stem cell and point of view of the microenvironment in which the stem cell resides."
The researchers have begun to combine their approaches, analyzing gene activity of the stem cells and the supportive cells at the same time. They noted, however, that it will take the interactive efforts of many groups to pin down the function of each gene. "We hope other groups will take up this challenge and share what they learn," said Lemischka.
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