What exactly makes a stem cell a stem cell? The question may seemsimplistic, but while we know a great deal of what stem cells can do,we don't yet understand the molecular processes that afford them suchunique attributes.
Now, researchers at Whitehead Institute for Biomedical Researchworking with human embryonic stem cells have uncovered the processresponsible for the single-most tantalizing characteristic of thesecells: 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 interestingfrom a therapeutic perspective," says Whitehead Member Richard Young,senior author on the paper which will be published September 8 in theearly online edition of the journal Cell. "They are wired so they canbecome almost any part of the body. We've uncovered a key part of thewiring diagram for these cells and can now see how this isaccomplished."
Once an embryo is a few days old, the stem cells start todifferentiate into particular tissue types, and pluripotency is foreverlost. But if stem cells are extracted, researches can keep them in thispluripotent state indefinitely, preserving them as a kind of cellularblank slate. The therapeutic goal then is to take these blank slatesand coax them into, say, liver or brain tissue. But in order to guidethem out of pluripotency with efficiency, we need to know what keepsthem there to begin with.
Researchers in the Whitehead laboratories of Young, RudolfJaenisch, MIT-computer scientist David Gifford, and the Harvard lab ofDouglas Melton focused on three proteins known to be essential for stemcells. These proteins, Oct4, Sox2, and Nanog, are called "transcriptionfactors," proteins whose job is to regulate gene expression.(Transcription factors are really the genome's primary movers,overseeing, coordinating, and controlling all gene activity.)
These proteins were known to play essential roles inmaintaining stem cell identity--if they are disabled, the stem cellimmediately begins to differentiate and is thus no longer a stem cell."But we did not know how these proteins instructed stem cells to bepluripotent," says Laurie Boyer, first author on the paper and apostdoctoral scientist who divides her time between the Jaenisch andYoung labs.
Using a microarray technology invented in the Young lab, Boyerand her colleagues analyzed the entire genome of a human embryonic stemcell and identified the genes regulated by these three transcriptionfactors. The research team discovered that while these transcriptionfactors activate certain genes essential for cell growth, they alsorepress a key set of genes needed for an embryo to develop.
This key set of repressed genes produce additionaltranscription factors that are responsible for activating entirenetworks of genes necessary for generating many different specializedcells and tissues. Thus, Oct4, Sox2, and Nanog are master regulators,silencing genes that are waiting to create the next generation ofcells. When Oct4, Sox2, and Nanog are inactivated as the embryo beginsto develop, these networks then come to life, and the stem cell ceasesto be a stem cell.
The new work provides the first wiring diagram of humanembryonic stem-cell regulatory circuitry. "This gives us a framework tofurther understand how human development is regulated," says Boyer.
"These findings provide the foundation for learning how tomodify the circuitry of embryonic stem cells to repair damaged ordiseased cells or to make cells for regenerative medicine," says Young."They also establish the foundation for solving circuitry for all humancells."
This research was funded by the National Human Genome ResearchInstitute and the National Institutes of Health. Richard Young consultsfor Agilent Technologies, manufacturers of his microarray platform.
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