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Duke Scientist Discovers Cell Structure Guides Potent, Reproductive Stem Cells

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Duke Health News 919-660-1306

DURHAM, N.C. -- In a discovery that may help answer the
riddle of how an amorphous sac of stem cells in testes gives
rise to sperm, Duke scientists have found a cell component that
appears to guide potent reproductive cells to both self-renew
and make mature differentiated cells.

The finding, in the common fruit fly, may help explain how
men continuously produce sperm, and why some stem cells in
testicles and other parts of the body lose control, forming
cancerous tumors.

Duke cell biologist Haifan Lin and his colleagues believe
the cell structure or "organelle" orchestrates the formation of
mature eggs from the progenitor stem cells in flies. This
organelle, which Lin dubbed the "spectrosome," appears to
direct and help determine which cells remain stem cells and
which become mature eggs by a process believed to be analogous
to human sperm production.

Lin and graduate student Wei Deng report their discovery in
a cover story in the Sept. 1 issue of the journal Developmental
Biology.

The research was supported by a grant from the National
Institutes of Health and by awards from the David and Lucille
Packard Foundation, the American Cancer Society and the March
of Dimes.

Lin discovered the structure while studying stem cells,
which are potent cells thought to produce most of the
specialized cells in the body, yet remain unchanged themselves.
Perhaps as few as a couple of dozen stem cells, for example,
give rise to all the varieties of white blood cells that
constitute the immune system, Lin said.

Researchers estimate stem cells form or maintain up to 90
percent of the tissues in our bodies. Yet how these immortal
cells work is one of the enduring mysteries of biology.

"The textbook version of cell division is that one cell
divides to produce two identical daughter cells," Lin said.
"But most of the cells in our bodies don't reproduce that way.
Most are replenished by stem cells."

The spectrosome, the researchers discovered, is made up of
structural proteins and anchors the stem cell to surrounding
"somatic" or body cells. During cell division, Lin and Deng
showed the spectrosome acts like a magnetic pole -- it
determines the orientation of the cells during division. The
spectrosome stays in the stem cell after division, but a tiny
piece gets pinched off in the daughter cell, which will then go
on to become the mature egg in subsequent cell divisions. Other
daughter cells become so-called feeder cells that nurture the
developing egg.

When the researchers knocked out a crucial gene that codes
for proteins that make the spectrosome, the stem cells could no
longer make eggs. Their cell divisions became randomly
oriented, as if the magnetic pole were missing. They could no
longer orient themselves.

Further, Lin showed for the first time that stem cells act
independently of each other; their cell divisions are not
coordinated. Previously, scientists had hypothesized that stem
cells coordinate their own activities -they take turns
dividing. But, Lin and Deng's work discounts that theory. They
found stem cells can divide at the same time at a frequency
indicating that their division is completely independent of
what neighbor stem cells are doing.

"This finding implies stem cells in tissues may be able to
act alone, in isolation from their siblings, an important
consideration for medical researchers who want to use only stem
cells to regenerate organs and tissues," Lin said.

In 1993, Lin was the first to identify true stem cells in
fruit flies, while working as a postdoctoral fellow in the
laboratory of Allan Spradling at Carnegie Institution of
Washington in Baltimore.

These stem cells are responsible for continuously generating
eggs in female flies in a specialized structure called the
germarium. The germarium produces eggs in an assembly line,
starting with an amorphous sac of cells that slowly grow and
change until a formed egg pops out the end. Lin used a laser
beam to kill cells in the germarium until he identified a few
cells that could regenerate the entire structure on their own.
Once he had identified these stem cells, he demonstrated that
these cells divide asymmetrically: to produce one cell like
itself and another that will differentiate to make a mature
egg. The finding was published in the June 1997 issue of the
journal Development.

Lin's discovery of how the sex cells -- sperm and eggs --
form in flies, may lead to a better understanding of sperm
formation in people. Human eggs, by contrast, are all formed
before birth and mature one at a time.

"No one has ever positively identified an individual stem
cell that makes sperm, yet one must exist, since sperm are
continuously formed throughout a man's life," Lin said. "Sperm
appear to be formed by a closely analogous process to the fly
egg production. Yet little is known about the process. This
finding may be a first clue."

Indeed, a May 30, 1996, Nature journal report from Ralph
Brinster and colleagues at the University of Pennsylvania
showed that donor cells from mouse testes could produce mature
sperm in an infertile recipient mouse, indicating stem cells
must exist in mouse testes and probably also in humans.

Abnormal division of stem cells is also responsible for many
forms of cancer, he said. Mutations in germ stem cells in
testicles account for some forms of testicular tumor formation,
according to Lin.

He believes an understanding of stem cell division and
coordination will lead to a better understanding of the
controls on cell growth and why some stem cells lose control to
form cancers.

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