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 not 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. This 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.
"We are studying the function of fruit fly genes in controlling stem cell division. Two such fly genes, "hedgehog" and "patched," have turned out to have counterparts in human cells that promote or suppress stem cell-derived skin cancer, respectively," Lin said. "We also have preliminary evidence that the spectrosome and other genes important in fly stem cells have counterparts in human cells as well."
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Journal
Developmental Biology