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Friday 5th November, 2004
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Scientists have successfully grown stem cells that make sperm,
which could lead to treatment of male infertility.
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PHILADELPHIA -- Researchers at the University of Pennsylvania School
of Veterinary Medicine have identified the growth factors essential to
allow spermatogonial stem cells -- the continually self-renewing cells
that produce sperm -- to exist in culture indefinitely. Their findings
will be presented this week in the Proceedings of the National Academy
of Science online Early Edition.
Spermatagonial stem cells and the hematopoietic stem cells that
generate new blood cells are the only types of adult stem cells that can
be positively identified using functional assays. Stem cells such as
these are called adult stem cells and are not the same as embryonic stem
cells. It may also be
possible to convert spermatogonial stem cells to totipotent cells,
capable of becoming almost any other cell type and similar to embryonic
stem cells.
Study details
After being kept in culture for three months, the stem cells restored
sperm production, and therefore fertility, in infertile mice.
Hiroshi Kubota, a research assistant professor of cell biology at the
Penn Veterinary school, developed the serum-free culture system that
enabled him, along with Brinster and researcher Mary R. Avabock, to
discover the essential ingredients that will sustain these cells. A
step-by-step additive process allowed them to determine that a single
growth factor, GDNF, was vital for promoting a signal-pathway that
allowed the cells to multiply in culture.
GDNF, the glial cell line-derived neurotrophic factor, was originally
identified as a survival factor for neurons in the brain. GDNF was also
found to be excreted by the Sertoli cells that surround and support the
spermatogonial stem cells in the testes. Once added to the culture, GDNF
caused the stem cells to form dense clusters and proliferate
continuously.
The Penn researchers then used a GFP marker gene in the cultured stem
cells to identify the cells before transplanting them back into
infertile mice. These mice then produced offspring that demonstrated the
success of the culture system, thanks to the expression of the GFP gene
that made the mice glow green under ultraviolet light. As in the mice
experiment, genetic changes to sperm stem cells are passed on to the
sperm, and, eventually, to any offspring produced from those sperm.
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According to the researchers, this development will have profound
consequences for future fertility therapies and provide a source of stem
cells that will make it possible to modify genes from males before they
are passed to the next generation. While the research was performed in
mice, the researchers believe that it is likely applicable to other
species, including humans.
"We've demonstrated that a central signaling process allows
spermatagonial stem cells to continually renew themselves, essentially
becoming immortal," said Ralph L. Brinster, a professor of reproductive
physiology at Penn. "For research, this opens up a wonderfully robust
diagnostic system for analyzing the function of individual genes. For
medicine, it opens up a new chapter in fertility medicine."
Whereas the female germ cell, the egg, stops dividing before birth,
the spermatogonial stem cells continue to divide throughout life.
According to Brinster, it is possible to modify the male germ line
between generations by manipulating the spermatogonial stem cells in
culture.
"If each parent in a couple carries a similar defective recessive
gene for a disease, for example, it should be possible in the future to
harvest the male spermatogenic stem cells, correct the gene in culture
and implant the stem cells back into the male to produce normal sperm,"
Brinster said. "The couple could then conceive a healthy child."
Likewise, the ability to culture spermatogonial stem cells indefinitely
allows for the possibility to create sperm in vitro, that is, without
implanting the stem cells in a recipient male. The technology could be
useful for correcting some types of infertility in which the testicular
environment is defective.
"The identification of the exogenous factors that allow these stem
cells to proliferate in culture establishes the foundation to study the
basic biology of spermatogonial stem cells," Kubota said.
Freezing sperm stem cells could also preserve them indefinitely. This
may allow men to save their sperm stem cells for future use, which could
help men facing chemotherapy preserve their fertility. Currently, men
facing infertility from chemotherapy can store their sperm before
treatment. However, the pregnancy success rate for frozen sperm is less
than 50%.
Funding for the research came from the National Institute of Child
Health and Human Development of the National Institutes of Health, the
Commonwealth and General Assembly of Pennsylvania and the Robert J.
Kleberg Jr. and Helen C. Kleberg Foundation.
Sources
SOURCES: Kubota, H. Proceedings of the National Academy of
Sciences, online edition. News release, National Institutes of
Health.
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