Researchers discover key to embryonic stem-cell potential
CAMBRIDGE, Mass. (September 8, 2005) - What exactly
makes a stem cell a stem cell? The question may seem
simplistic, but while we know a great deal of what stem
cells can do, we don't yet understand the molecular
processes that afford them such unique attributes.
Now, researchers at Whitehead Institute for Biomedical Research working with human embryonic stem cells have uncovered the process responsible for the single-most tantalizing characteristic of these cells: 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 Richard Young, senior author on
the paper which will be published September 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."
A few days after the egg cell has been fertilized, the stem cells start to differentiate into particular tissue types, and pluripotency is forever lost. But if stem cells are extracted, researches can keep them in this pluripotent state indefinitely, preserving them as a kind of cellular blank slate. The therapeutic goal then 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.
"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,"
says Whitehead Member Richard Young. |
Researchers in the Whitehead laboratories of Young,
Rudolf Jaenisch, MIT-computer scientist David Gifford,
and the Harvard lab of Douglas Melton focused on three
proteins known to be essential for stem cells. 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.)
These proteins 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.
Using a microarray technology invented in the Young
lab, Boyer and her colleagues analyzed the entire genome
of a human embryonic stem cell and identified the genes
regulated by these three transcription factors. The
research team 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 then come to life, and the stem cell ceases
to be a stem cell.
The new work provides the first wiring diagram of human
embryonic stem-cell regulatory circuitry. "This
gives us a framework to further understand how human
development is regulated," says Boyer.
"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," says Young, who also
is a professor of biology at MIT. "They also establish
the foundation for solving circuitry for all human cells."
This research was funded by the National Human Genome
Research Institute and the National Institutes of Health.
Richard Young consults for Agilent Technologies, manufacturers
of his microarray platform.
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