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DURHAM, N.C. – Duke University Medical Center cell biologists have
defined a signaling system between stem cells and the specialized
"niche cells" that harbor and regulate them. The findings provide
better understanding of the signals that stimulate stem cells to either
create more copies of themselves or to differentiate into another cell
type, said the researchers.

Germline stem cells are immature
cells in the reproductive system that can proliferate and mature into
sperm and eggs. While it is has been appreciated that these stem cells
exist in a microenvironment attached niche cells, it has not been well
understood how these two cell types communicate.

In their latest
study, the results of which were published in the Jan. 26, 2005, issue
of the journal Current Biology, the Duke team reported that regulatory
genes from niche cells instruct genes in stem cells to determine the
future path of the stem cells. Both niche and stem cells possess genes
which produce proteins that act as a series of "on-off" switches for
stem cell division, the researchers said. The research was supported by
the National Institutes of Health.

Over-proliferation of stem
cells is one of the leading causes of cancer, while reduced stem cell
production is implicated in such disorders as infertility, anemia and
immune system deficiencies.

It is important to understanding how
stem cells receive their cues to differentiate, the researchers
continued, because any potential future clinical application of stem
cells cannot focus on them alone, but must also take into account the
role of niche cells.

For their experiments, researchers led by
Duke cell biologist Haifan Lin, Ph.D. studied germline stem cells from
the ovaries of the common fruit fly Drosophila. They analyzed the
expression of specific genes as the germline stem cells either created
additional copies of themselves or differentiated into another cell
type known as a cystoblast, which eventually become mature eggs.

"We
found that stem cells behavior is regulated by the neighboring niche
cells, which provide an idyllic hideaway essential to the functioning
of the stem cells," Lin said. "Stem cell division is an asymmetric
process. After division, one daughter cell remains attached to the
niche cell and thus remains as a stem cell, whereas the other daughter
cells is detached from niche cells and will thus acquire a different
fate."

Lin's team determined three different genes -- piwi,
pumilio (pum) and bam (bag of marbles) – that mediate the interplay
between stem cells and niche cells that controls stem cell fate. It has
been known that piwi and pum must be activated for successful
self-renewal of germline stem cells, while bam is essential for
cystoblast differentiation. Piwi, initially discovered in the Lin lab,
is the founding member of a family of genes involved in the development
stem cells in diverse organisms in both animal and plant kingdoms. pum-
and bam-like genes also exist in mammals and humans.

"In our
experiments we demonstrated that piwi and bam proteins are expressed
independently of each other in reciprocal patterns in germline stem
cells and cystoblasts," Lin said. "However, overexpression of either
one of these genes antagonizes the action of the other in these cells,
acting as on-off switches."

According to their new model of niche
cell-germline stem cell interaction, activation of the piwi gene in
niche cells leads to the production of proteins that block the
expression of bam in germline stem cells. The absence of an active bam
gene causes pum, and other genes in the stem cells, to become active.
The pum gene then prevents the production of proteins involved in
differentiation.

"The result of this sequence of events is the
suppression of differentiation, which maintains the fate of the cell as
a germline stem cell," Lin said.

In the cystoblast cell, the
signal from piwi is no longer effective because this cell is detached
from niche cells, which allows for the expression of the bam gene,
which in turn represses the activity of pum, allowing the cell to
differentiate.

"Therefore, pum can be considered as the switch
between self-renewal or differentiation, and signaling from niche cells
through bam regulates this switch at the single cell level," Lin
explained.

As they have done in their previous studies using the
Drosophila model, Lin's team is also using the mouse model to determine
whether or not the same signaling pathways are present in higher
organisms.

Interestingly, they said, while the piwi gene plays an
important role in determining germline stem cell differentiation in
Drosophila, its equivalent in mice, miwi, has been shown to be the key
gene involved in development of sperm cells. In humans, Lin's team
discovered in 2002 that overexpression of the hiwi gene, a piwi-like
gene in human, has been implicated in the development of a common form
of testicular cancer, while underexpression can lead to infertility.

First authors of the paper were Akos Szakmary, Ph.D., Duke, and Daniel Cox, Ph.D., now at George Mason University, Manassas, VA.