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8-Humans: Embryonic stem cells turned into eggs

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TITLE:  Embryonic stem cells turned into eggs
SOURCE: The New Scientist, UK, by Sylvia Pagan Westphal
DATE:   May 1, 2003

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Embryonic stem cells turned into eggs

Embryonic stem cells have been turned into egg cells - the first time
scientists have duplicated the process of egg formation and ovulation in
the test tube.

The feat was achieved with embryonic stem cells (ESCs) from mice, but
most experts see no reason why the same should not work in humans. If so,
this opens the possibility that human eggs could be made in large numbers
in a culture dish, instead of relying on donors.

That could advance research on infertility, the understanding of
menopause and even help perfect the process of cloning, says Jose Cibelli
of Michigan State University in the US. "It's terrific," he says. "Eggs
were one of those cell types we never thought we could produce."

The work also proves that ES cells are "totipotent". This means they can
give rise to every tissue in the body, including those used for reproduction.

"The work is exceptional," adds researcher Gerald Schatten from the
University of Pittsburgh, Pennsylvania. "The results convincingly
demonstrate that ESCs from mice have universal, not just restricted,
developmental capabilities."

High density

Several groups of researchers were trying to make eggs from ESCs, but
with little success. In the end, the key was straightforward - letting
nature take its course.

Instead of searching for special chemical factors to coax ESCs into
becoming eggs, Hans Schoeler of the University of Pennsylvania and his
colleagues let ESCs grow in basic conditions but at a high density. "The
procedure is just too simple," he says. "There's no complicated cocktail
of growth factors."

Growing at high density, some of the cells detach from the lab dish and
form floating aggregates. The clumps look like the type of debris most
scientists would probably throw away, says Schoeler.

But researcher Karin Huebner took those clumps and placed them in new
dishes, adds Schoeler: "She found that in four days they proliferated
like crazy." As it turned out, those aggregates were like miniature
ovarian structures, each with small cells nurturing a bigger cell that
was to become the egg.

Ovulation simulation

Schoeler's team not only followed the aggregates morphologically, but
monitored the expression of key genes and saw they were turned on as
expected during egg development. The miniature ovarian structures even
started to make hormones like estradiol, with production peaks similar to
those of the menstrual cycle.

Strikingly, adding another kind of hormone called gonadotropin to the
mini-ovaries induced the expulsion of an egg cell into the culture dish,
mimicking ovulation.

The eggs themselves appeared normal in many ways, including appearance,
size and gene expression. If cultured for a few days, the eggs also
underwent spontaneous division and formed structures resembling embryos,
a process known as parthenogenesis. That, says Schoeler, hints that the
eggs are functional. His immediate plans include testing whether the eggs
can be fertilised with sperm.

Before the findings can be extrapolated to any human applications,
experts warn that extensive studies will need to be done to make sure
that eggs produced in the laboratory are truly equivalent to real eggs.

For example, Schoeler's group produced eggs from both male and female
ESCs so it will be important to see whether the eggs have the correct
pattern of "imprinting". This set of molecular cues convey female
identity to the DNA in an egg and are key for proper embryo formation.
"There is always a possibility that the imprints would not be normal,"
says Azim Surani from the University of Cambridge, UK.

Journal reference:Science (DOI: 10.1126/science.1083452)