Interaction between stem cells and their niches key to differentiation

January 25, 2005

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.
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Duke University Medical Center

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