Composed of lymph vessels, lymph nodes and organs, the lymphatic system absorbs excess fluid and returns it to the bloodstream, absorbs fat in the villi of the small intestine and works with the immune system. A parallel system to blood vessels, the lymphatic system acts as a conduit for everything from immune cells to fat molecules to cancer cells.
Lymph vessels are associated with circulatory system vessels, and larger lymph vessels are similar to veins. Lymph capillaries are found all over the body. When skeletal muscles contract, lymph fluid moves through valves.
Dr. Karina Yaniv of the Weizmann Institute's Department of Biological Regulation in Rehovot, Israel, has been studying the lymphatic system for 20 years. She focuses on examining how blood and lymphatic vessels form during embryonic development. During her postdoctoral studies, Dr. Yaniv showed that, contrary to common belief, zebrafish do have a lymphatic system. Now she and her colleagues -- supported by the Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics; the Karen Siem Fellowship for Women in Science; the Carolito Stiftung; the Adelis Foundation; the David M. Polen Charitable Trust; and the estate of Georges Lustgarten - are growing lymphatic cells in the laboratory for the first time.
In a study reported in the May 20 issue of Nature, Dr. Yaniv and her colleagues explained how the lymphatic system develops in the embryo. While growing the world's first lymphatic cells in the lab, they discovered that these cells grow from veins, but originate from a place in the vein that contains angioblasts. The research was performed in collaboration with the laboratories of Prof. Itai Yanai from the Technion - Israel Institute of Technology, Dr. Jacob Hanna of Weizmann's Department of Molecular Genetics and Prof. Nathan Lawson of the University of Massachusetts.
According to the article, entitled, "Lymphatic vessels arise from specialized angioblasts within a venous niche," the researchers discovered that "multipotent progenitors undergo cell-fate restriction in response to cues from the microenvironment, the nature of which is poorly understood." Further, the authors wrote, "Here we show that in zebrafish, lymphatic progenitors arise from a previously uncharacterized niche of specialized angioblasts within the cardinal vein, which also generates arterial and venous fates. We further identify Wnt5b as a novel lymphatic inductive signal and show that it also promotes the ‘angioblast-to-lymphatic' transition in human embryonic stem cells, suggesting that this process is evolutionarily conserved."
At the beginning of the research project, Julian Nicenboim and Dr. Guy Malkinson of Dr. Yaniv's team procured images of developing zebrafish embryos. The transparent bodies of these embryos make it possible to document their development in real time during the course of several days. Then the scientists played the movies backward, in order to determine the point at which the lymphatic system began to form. According to the report in Nature, they were surprised to discover that "the cells that give rise to lymphatic vessels always originated in the same part of the embryo's major vein." In that location, the scientists discovered a niche of angioblasts, the same cells that had been considered to be the source of lymph vessels at one time.
After performing an in-depth genetic analysis with the help of graduate students Tal Lupo and Lihee Asaf, the researchers came up with the idea that a gene called WNT5B was the causal agent that prompted stem cells to differentiate into lymphatic cells. When postdoctoral fellow Dr. Yogev Sela added WNT5B to human embryonic stem cells, the cells differentiated into lymphatic cells, making it the first time such cells had ever been grown in the lab.
As Dr. Yaniv explained, "We started out by imaging zebrafish, and ended up finding a factor that makes it possible to create lymphatic cells. That's the beauty of research in developmental biology: The embryo holds the answers, and all we have to do is watch and learn."
In addition to answering the longstanding question of how the lymph system arises, understanding how it forms and develops can provide important insights into disease, from the metastasis of cancer to the abnormal accumulation of lymph fluids, especially after surgery to remove cancerous tumors. The main reason why people die of cancer is that the cancer cells spread to form daughter tumors, or metastases, in vital organs, such as the lungs and liver. A route frequently used by cancer cells for dissemination is the lymphatic system. From there they spread to other organs by way of the blood. The details of how and why cancer cells use the lymphatic system are relatively unknown, but Dr. Yaniv's research can provide some vital clues.
Dr. Yaniv's research may, in the future, lead to new therapies for heart disease, stroke, cancer and other illnesses. "I think it's imperative for us to learn how to manipulate vessel growth," she said. "Sometimes we want to encourage vessel growth and sometimes we want to stop it."
