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What Makes a Stem Cell a Stem Cell?
By Nancy Touchette

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The potential of stem cells in treating disease has put them at the center of a lively and often heated debate in both scientific and political circles. Stem cells, in principle, could be cultured to produce replacement cells for the treatment of a wide variety of medical conditions, including diabetes, heart disease, stroke, neurodegenerative diseases, and spinal cord injury.

While many researchers maintain that only stem cells derived from embryos have the potential to become all types of human cells, others suggest that stem cells derived from adult tissues can serve the same purpose without the ethical ramifications.

Detail from diagram showing profiling of stem cells. View full

Indeed, stem cells derived from bone marrow have recently been coerced into becoming liver, brain, muscle, and heart cells. And stem cells found in muscle have reportedly been coaxed into becoming blood cells. These experiments suggest that adult stem cells may be more plastic than previously thought and they raise the question: What makes a stem cell a stem cell?

A stem cell, by definition, can renew itself and can generate myriad types of specialized cells. But the specific genes that confer these properties remain unknown. To address the issue, two teams of researchers independently attempted to identify a set of genes that defines a stem cell.

Using DNA microarray technology, the researchers looked for genes that are turned on, or expressed, in mouse stem cells compared to cells that have already specialized (and are unable to become different types of cells). Both research teams analyzed genes expressed in three types of mouse cells: embryonic stem cells derived from mouse embryos, neural stem cells derived from brain tissue, and hematopoietic stem cells derived from bone marrow.

‘Is there any cell in the world that has a molecular signature?’

One team, led by Douglas Melton of Harvard University in Cambridge, Massachusetts, identified 216 genes that are turned on in all three types of stem cells. The other team, led by Ihor Lemischka of Princeton University in New Jersey, identified 283 genes expressed in the cell types.

"What is the essence of being a stem cell? This is a question the stem cell community has been asking for a while," says Evan Y. Snyder, who investigates stem cells at Harvard Medical School in Boston. "This research is a good first step toward allowing us to develop molecular fingerprints of these cells."

An indication of the difficulty of answering this question is that both research teams found different sets of genes that were 'common' to stem cells. Less than ten percent of the genes they each identified were the same between both studies. Indeed, some researchers question whether it is even possible to identify a unique set of genes that can define a stem cell.

"Is there any cell in the world that has a molecular signature?" says Ronald McKay, who investigates stem cells at the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland. "An embryonic stem cell this morning might be different than an embryonic stem cell tonight. These systems are quite complex, and genes are being turned on and off quite readily."

McKay adds that it may be difficult to compare the two new studies, both published in Science, because the groups looked at different sets of genes and used different statistical methods to analyze the results.

Nonetheless, there was common ground: Both groups of researchers found a characteristic set of genes expressed in each type of stem cell that was unique to that particular cell type. In addition, they found a subset of genes that were active in all three types of cells.

Based on their results, the Harvard researchers propose several essential attributes that they believe underlie the stem cell's ability to reproduce itself and to generate different types of specialized cells. Key among these is the ability to resist stress from the environment by activating enzymes that repair DNA and detoxify cells. Stem cells also express genes important in regulating the cell cycle and in helping cells to communicate.

The Princeton researchers examined what genes were turned on and off as bone marrow stem cells matured to different types of specialized blood cells. Genes that regulate communication among cells are turned on in stem cells. Specialized blood cells express genes that control the cell's life cycle, repair DNA, and manufacture proteins.

It may be some time, however, before researchers fully understand what constitutes "stemness." According to some researchers, genomic analyses may be yielding too much information.

"At this stage, the findings are really more like a telephone directory," says Snyder. "We've got all these entries, but we don't know what they mean. We would really like to see them organized in terms of function, like the blue pages."

Many different laboratories have analyzed gene expression in stem cells using DNA microarray technology, and some with puzzling results. "What we really need to do is get together and compare results and see what players come up time and time again," says Snyder. "We can't bet on the whole stable. We need to pick a few horses and ride with them."

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Ivanova, N.B. et al. A stem cell molecular signature. Science 298, 601-604 (October 18, 2002).
Ramalho-Santos, M. et al. "Stemness": Transcriptional profiling of embryonic and adult stem cells. Science 298, 597-600 (October 18, 2002).
Ourednik, J. et al. Neural stem cells display an inherent mechanism for rescuing dysfunctional neurons an inherent mechanism for rescuing dysfunctional neurons. Nat Biotechnol. Published online October 15, 2002.
Park, K.I. et al. The injured brain interacts reciprocally with neural stem cells supported by scaffolds to reconstitute lost tissue. Nat Biotechnol. Published online October 15, 2002.
Kim, J.-H. et al. Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease. Nature 418, 50-56 (July 4, 2002).

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