PA) - At some point in fetal development, cells from
the newly emerged blood circulatory system start out
on their own and form a separate parallel network of
vessels known as the lymphatic system. In the January
10th issue of Science, researchers from the University
of Pennsylvania School of Medicine report the discovery
of the molecular signals necessary to separate the lymph
vessel network from the blood vessel network.
Their findings clarify an important juncture
in fetal development, shed light on the mechanisms by
which molecular signals influence vascular development,
pave the way for potential therapeutics, and may ultimately
clear up a minor mystery among researchers that has
been brewing since the mid-1990s.
"According to our studies, the SLP-76
and Syk proteins, which we previously knew to have a
signaling function in white blood cell development,
are absolutely critical in separating the lymphatic
system from the circulatory system," said Gary
Koretzky, MD, PhD, professor in Penn's Department
of Pathology and Laboratory Medicine and director of
the Signal Transduction Program at the Abramson Family
Cancer Research Institute. "This new role is important
if we are ever to learn how to influence the growth
of blood or lymphatic vessels. For example, under some
clinical circumstances, it would be useful to encourage
the growth of new blood vessels or, conversely, discourage
new vessels from supplying blood to growing tumors."
Since the mid-1990s, researchers have been trying to
determine the exact function of SLP-76 and Syk. The
proteins are related signals involved in hematopoiesis
- the process by which stem cells transform into red
and white blood cells. To better understand the function
of these signals, several groups created animal models
that lacked SLP-76 or Syk in order to see what happens
in their absence. Researchers in Koretzky's laboratory
found that most animal models lacking SLP-76 had severe
abnormalities in white blood cell development.
Additionally, the animal models that grew
to adulthood had larger than normal hearts. A conversation
with Mark L. Kahn, MD, assistant professor in the Division
of Cardiology in Penn's Department of Medicine led to
a collaborative investigation of what was happening.
"In humans, increased heart size and cardiac
output can result from anemia, heart defects, or the
shunting of blood into inappropriate channels. The animal
models were neither anemic nor had heart defects, so
our attention turned to the vasculature," said
Kahn. "In essence, we found that blood was being
forced into the lymphatic system. Their hearts were
larger because the lymphatic channels mediated arterio-venous
shunting of blood."
Kahn and Koretzky tracked the shunting to an abnormality
in the abdomen that tied the blood vasculature to the
lymphatic vasculature. Mammals have two circulatory
systems - a closed blood vasculature and an open lymphatic
vasculature. The blood circulatory system is the body's
main transportation system, delivering oxygen and nutrients
throughout the body. The lymphatic system serves as
a collecting duct for excess fluid and as a filtering
system to screen out foreign organisms.
"In SLP-76 deficient animal models, the two systems
never separate during fetal development," said
Kahn. "Remarkably, pictures taken of the blood
pushing its way into the lymphatic system closely resembles
that of pictures drawn by Florence Sabin over 100 years
ago when she first researched and described the fetal
development of the lymphatic system."
The researchers obtained similar results in studying
animals that lacked Syk, a signaling protein similar
to SLP-76. Syk, SLP-76, and related signaling proteins
are highly influential in the development of hematopoetic
cells in adults and now, as it would seem, in developing
"It is becoming increasingly clear that the regulation
of signal transduction is critical for understanding
both basic biological processes and the diseases that
occur as these processes go awry," said Koretzky.
"Only now are we really beginning to understand
the clinical potential these molecular signals may have
in fighting disease."
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The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2016 fiscal year.
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