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Researchers Map Protein Network that Regulates “Stemness”
Wednesday, 15 November 2006
Howard Hughes Medical Institute (HHMI)
researchers have created a map that charts the largely unexplored protein
landscape that regulates a stem cell's ability to differentiate into
multiple types of mature cells.
Understanding this protein network in greater detail could give stem cell
biologists a new set of tools to coax mature cells to revert to an
embryonic state, said the researchers. Reprogramming adult cells in this
way could provide an alternative source of stem cells to use in
regenerating tissues damaged by disease or trauma, rather than employing
embryonic cells, they said.
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Prof.
Stuart Orkin, M.D..
Photo by the courtesy of Samuel Ogden.
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HHMI investigator Stuart
Orkin and his colleagues at Children's Hospital Boston and Harvard Medical School
published their findings November 8, 2006, in an advanced online
publication in the journal Nature.
Orkin said that thus far experiments aiming at reprogramming mature cells
into a stem cell-like state have yielded cells that imperfectly resemble
embryonic stem cells.
“However, with this new understanding
of the network of regulatory factors, it might be possible to refine this
approach to reprogramming,” he said.
The regulatory network that maintains a stem cell's ability to become many
different cell types — a characteristic called pluripotency — also prevents the cell from inappropriately
differentiating into a mature cell, while keeping it poised to undergo
maturation when required. This precise control relies on intricate circuits
of interacting proteins that both regulate one another and govern the
activity of genes.
To create a detailed map of this network, the researchers used mouse
embryonic stem cells. Orkin noted that although the researchers used mouse
embryonic stem cells as their model, the circuitry regulating pluripotency
is likely similar in all stem cells.
As the jumping-off point of their mapping effort, Orkin and his colleagues
used a protein called Nanog, which other researchers' experiments had
indicated was central to regulation of stem cell pluripotency. The
researchers first tagged Nanog so that when they removed it from cells,
they would simultaneously remove any proteins that were attached to it.
These experiments enabled them to identify numerous proteins that interact
with Nanog, including some already known to regulate pluripotency. To
confirm that the proteins they had found functioned to maintain stem cell pluripotency,
they depleted the levels of several proteins in embryonic cells and
observed that the cells then expressed markers of differentiation.
Next, the researchers created a protein interaction map that showed the
relationships among the various proteins. The map will provide stem cell
biologists with an important guide for future studies, said Orkin.
“Even though some of these factors
were known to be important in pluripotency, exactly how they work and who
they talk to and interact with was completely unknown,” he said.
Orkin said the fact that so many of the proteins seemed to be concentrated
in a single self-contained regulatory circuit came as a surprise. The
proteins in the network seem to be regulated as a group in embryonic cell
differentiation. Also, many proteins work closely together in complexes
that repress genes that trigger stem cell differentiation.
“It could well have been that some of
these proteins were distributed elsewhere in the cell proteome, and that
they interacted with other factors that only subsequently converged in the
genes that they regulated. But instead, our findings suggest that not only
do these proteins interact with the target genes together in various ways,
but they are also continuously talking to one another as proteins. Thus,
this seems to be a sort of holistic network that is almost grafted onto the
rest of the cellular machinery.”
“The whole network is very
convoluted. The proteins are not only regulating one another, but many of
their genes are regulatory targets of the same proteins,” said Orkin.
“So, in one sense the system is
stable because the proteins are interdependent, but on the other hand it is
unstable, because if you take out a critical element, the whole circuit
falls apart. But having such a tightly controlled, interdependent circuit
makes sense, because the stem cell doesn't want to be completely frozen as
a stem cell — it has to be poised to differentiate in response to the right
signals.”
The intimate contact between the proteins in the network should make it
easier to characterize their function and identify additional members, he
said. Orkin added that thorough understanding of the characteristics of
pluripotent embryonic stem cells is the field's “gold standard.”
“We would like to understand as much
as we can about the network of components required to establish and
maintain pluripotency, because it might be feasible to establish that whole
network within a somatic cell and reprogram it to closely resemble an
embryonic stem cell,” he said.
“The major controversy over using
human embryonic stem cells is that it requires obtaining oocytes and
perhaps destroying embryos,” said Orkin.
“However, if one could reprogram,
say, a skin cell to revert to become identical to an embryonic-type cell,
it would obviate these ethical issues.”
Source: Howard Hughes Medical Institute, MA
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