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First-Ever Recording of Blood Vessel Development During the Formation of an Organ

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Duke Health News 919-660-1306

DURHAM, N.C. -- A new microscope system that can take 3-D
pictures of an embryonic mouse organ over 24 to 48 hours has
shown Duke Medical Center researchers the first glimpse of the
formation of blood vessels during development.

Among other things, a team lead by cell biologist Blanche
Capel, Ph.D., has found a previously unknown mechanism in the
formation of blood vessels that may help scientists better
understand how a tumor rallies a blood supply to its aid.

Using mice that have blood vessel cells marked by green
fluorescence, the Duke University cell biologists studied
vessels that supply mouse gonads. These are the embryonic
organs that give rise to ovaries or testes later in
development.

The team studied gonads because they could remove and
culture the gonad along with the nearby tissue that initially
houses the major blood vessels. This way they could watch how
the blood vessel system (vasculature) develops as the gonad
changes into a testis or ovary.

The scientists' novel system for studying development using
time-lapse microscopy and tiny samples of tissue shed new light
on the dynamic process of organ formation. This system answered
key questions about how the vasculature gets fitted into the
organ as it forms, Capel said. Before this, scientists could
only image one point in development at a time.

The striking new images became the cover story of the
Proceedings of the National Academy of Sciences and were
assembled into a time-lapse movie.

The research was funded by grants from the National
Institutes of Health Heart, Lung and Blood Institute and the
Lalor Foundation.

The Duke team was surprised by the vigorous cell movements
involved in the development of male gonads. "In the male gonad,
the major blood vessel in the adjacent tissue comes apart and
the individual blood vessel cells move to a new location, and
reassemble into new vessels inside the testis," Capel said.
"This breakdown process represents a possible way for growing
tumors to access a blood supply, by commandeering a mechanism
similar to the ones organs use to recruit vessels into the
tumor."

She pointed out that a blood supply is critical to a growing
tumor, and this may be an important mechanism in the formation
of blood vessels in tumors that scientists have not appreciated
before. "That is an exciting finding," Capel said.

This imaging in 3-D over time was possible because Capel's
laboratory already had developed a culture system for studying
the organ in the lab. "We were positioned to convert that to a
live imaging system when advances in microscopy became
available at Duke University Medical Center," Capel explained.
"The Duke Department of Cell Biology has an imaging facility
that is really outstanding, and our chair, Brigid Hogan, has
put a lot of energy into making sure it is state of the art.
One of the authors on this paper, Tim Oliver, who manages this
facility, helped us to get the imaging set up."

The organs were placed in small wells in an agar block
designed to hold them still. The entire system was enclosed in
a humidified and temperature-controlled chamber around the
microscope. Scientists captured an image every 20 minutes for
24-48 hours, then later assembled the images in sequence to
make movies.

It wasn't easy, Capel said. "We had to work a lot of kinks
out of the system. For example, we were exposing the organ to a
laser to detect the fluorescent vascular cells throughout the
duration of the culture. But too much laser light damages
cells. You need to create a bright enough fluorescence in the
cells so that you don't have to turn the laser on such a high
setting that it kills cells during the culture period."

This success with recording the growth of blood vessels has
spurred the Capel lab team on to new projects. "Our goal now is
to have different colored fluorescent markers for other types
of cells in the organ. I hope we can simultaneously image the
vessels and other cells as the vessels move into the organ, so
we can see how they interact together as a functional organ is
forming."

Other authors on the paper include Douglas Coveney, Ph.D.,
and Jonah Cool, a doctoral student, both in the Capel
laboratory at the Duke Department of Cell Biology.

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