September 28, 2001
Blood Vessels Trigger Development of the Pancreas
Scientists have known that developing organs communicate with blood
vessels via chemical signals to ensure that they receive the proper
blood supply to sustain growth. Now, researchers have discovered that
blood vessels can send signals that trigger development of the
pancreas. The finding provides the first glimpse of a new type of
biochemical signaling pathway that may prevent the pancreas, and
possibly other organs, from developing until a blood-supply pipeline is
in place.
According to the researchers, the source of the blood vessel signal
may prove useful to scientists who are hoping to guide the
differentiation of embryonic stem cells into pancreatic islet cells,
the insulin-producing cells that are depleted in people who have type I
diabetes. The discovery was published September 28, 2001, in the
journal Science, as part of the Science Express Web
site.
“What jumped out was that we could never find any evidence for pancreas development or differentiation when there wasn’t a blood vessel touching [the pancreas].”
Douglas A. Melton
“Other biologists might already have thought of the
possibility of such signaling, but it was definitely a surprise to
me,” said Douglas
A. Melton, a Howard Hughes Medical Institute investigator at
Harvard University. According to Melton, insights from histological
studies provided the initial evidence that led them to search for blood
vessel signaling.
“When we used histological sections to examine how the
pancreas develops, what jumped out was that we could never find any
evidence for pancreas development or differentiation when there
wasn’t a blood vessel touching it,” he said. “Also,
it has been long known that in mice the pancreas develops by initially
forming three buds, which are subsequently reduced to two. These
remaining two buds fuse to form the whole pancreas. We’d always
been puzzled about why the third bud disappears, and our examinations
showed that this bud invariably loses its contact with a blood vessel.
Taken together, these studies indicated to us that pancreatic
development is closely linked with the presence or absence of blood
vessels.”
Melton and colleagues Eckhard Lammert and Ondine Cleaver did three
types of experiments that provided additional evidence that blood
vessel endothelial cells transmit signals to embryonic endodermal cells
that develop into tissues such as the pancreas.
In cell culture studies, Melton and his colleagues found that
isolated, cultured endoderm cells showed no signs of becoming
pancreatic cells as they grew. When the scientists added cells from the
dorsal aorta — a vessel that lies next to those cells in the
developing embryo — the endoderm cells began expressing insulin and
the gene, Pdx1, which is a known marker of pancreatic
differentiation.
In experiments using frog embryos, the scientists found that when
they removed blood vessels that were adjacent to pancreatic tissue, the
embryos did not show normal expression of genes or insulin production
that would be characteristic of normal pancreas differentiation.
Finally, the scientists created transgenic mice in which the gene
VEGF164, which triggers blood vessel development, was
overexpressed. In these studies, the scientists found that a dramatic
increase in blood vessel endothelial tissue accompanied a similar
increase in pancreatic islet cells. The researchers also found
insulin-producing cells in the stomachs of the mice – an area
where such cells would not normally appear. The three lines of evidence
warrant a rethinking of the role of blood vessels in organ development,
said Melton.
“The fact that all tissues and organs in the body need blood
has led many biologists, including myself, to consider blood vessels as
tubing that provides sustenance for the body,” he said.
“But beyond that, there are a special set of organs or tissues in
the body that use blood to serve their basic functions. These include
hormone-secreting endocrine glands, lungs, kidneys, the liver and the
pancreas.
“So, these organs must arrange for intimate contact with
vessels,” he said. “To do this, they could develop first
and then send signals to blood vessels to come to them – as
tumors do in the process of angiogenesis. Or, these organs could also
use a mechanism involving signals from blood vessels to trigger their
differentiation, to guarantee this intimate contact before they
develop.”
Given the new findings that blood vessels signal pancreatic cells,
Melton expects a similar signaling system to be found in other organs.
While the discovery of this signaling mechanism will most likely aid
efforts to trigger stem cells to become islet cells, which may be used
to treat diabetes, Melton emphasizes that blood-vessel-signaling
constitutes only one factor governing differentiation.
“This is not the answer by itself to the problem of making
islet cells,” he said. “But it is an important finding
because it reveals one of the signals in a stepwise path in islet cell
differentiation,” he said.
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