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Scientists discover key to embryonic stem-cell potential

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Researchers from MIT, the Whitehead Institute for Biomedical Research, and colleagues have discovered the process responsible for stem cells' single-most tantalizing characteristic: their ability to become just about any type of cell in the body, a trait known as pluripotency.

"This is precisely what makes these stem cells so interesting from a therapeutic perspective," says Whitehead member and MIT biology professor Richard Young, senior author of a paper on the work published Sept. 8 in the early online edition of the journal Cell. "They are wired so they can become almost any part of the body. We've uncovered a key part of the wiring diagram for these cells and can now see how this is accomplished."

"These findings provide the foundation for learning how to modify the circuitry of embryonic stem cells to repair damaged or diseased cells or to make cells for regenerative medicine," Young continued. "They also establish the foundation for solving circuitry for all human cells."

Once an embryo is a few days old, the stem cells start to differentiate into particular tissue types, and pluripotency is forever lost. But if stem cells are extracted, researchers can keep them in this pluripotent state indefinitely, preserving them as a kind of cellular blank slate. The therapeutic goal is to take these blank slates and coax them into, say, liver or brain tissue. But in order to guide them out of pluripotency with efficiency, we need to know what keeps them there to begin with.

Researchers in the laboratories of Young, MIT biology professor and Whitehead member Rudolf Jaenisch, MIT professor of electrical engineering and computer science David Gifford, and Harvard's Douglas Melton focused on three proteins known to be essential to stem cells. (Gifford and Melton are also affiliated with the Broad Institute of MIT and Harvard.)

These proteins, Oct4, Sox2 and Nanog, are called "transcription factors," proteins whose job is to regulate gene expression. (Transcription factors are really the genome's primary movers, overseeing, coordinating, and controlling all gene activity.)

The three were known to play essential roles in maintaining stem cell identity -- if they are disabled, the stem cell immediately begins to differentiate and is thus no longer a stem cell. "But we did not know how these proteins instructed stem cells to be pluripotent," says Laurie Boyer, first author on the paper and a postdoctoral scientist who divides her time between the Jaenisch and Young labs.

To that end, Boyer and colleagues analyzed the entire genome of a human embryonic stem cell and identified the genes regulated by these three transcription factors. They discovered that while these transcription factors activate certain genes essential for cell growth, they also repress a key set of genes needed for an embryo to develop.

This key set of repressed genes produce additional transcription factors that are responsible for activating entire networks of genes necessary for generating many different specialized cells and tissues.

Thus, Oct4, Sox2 and Nanog are master regulators, silencing genes that are waiting to create the next generation of cells. When Oct4, Sox2 and Nanog are inactivated as the embryo begins to develop, these networks come to life, and the stem cell ceases to be a stem cell.

This research was funded by the National Human Genome Research Institute and the NIH.

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