Separated Before Birth: Molecular Signals Part Fetal Blood and Lymphatic Vessels

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 fetuses.

“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.”