Scrutiny of fluorescently labeled zebrafish embryo blood vessels revealed that angioblasts tucked within the cardinal vein give rise to lymphatic vessels. [Weizmann Institute of Science]
Scrutiny of fluorescently labeled zebrafish embryo blood vessels revealed that angioblasts tucked within the cardinal vein give rise to lymphatic vessels. [Weizmann Institute of Science]

A durable Roman proverb—“It would be easier to find the source of the Nile”—may have occurred to scientists seeking the origins of the lymphatic system. Not only were these origins as obscure as a shifting maze of marshy channels, they gave rise to long-running disputes. Close to a century ago, two competing proposals for the lymphatic system’s origin emerged, and although one gained broad acceptance, the other was never entirely discounted.

Some scientists claimed that the lymphatic system was derived from specialized stem cells called angioblasts, whereas others argued that it originated by the differentiation of preexisting embryonic veins. The latter model ultimately became the accepted view.

New research, however, suggests that there is truth in both views, which may seem less surprising one likens the difficulty in delineating fluid flows to the difficulty in following the subtle differentiation events by which multipotent embryonic cells acquire recognizable cellular identities. These differentiation events attracted the attention of a group of scientists at the Weizmann Institute, who were as intrepid, in their own way, as the Victorian-era explorers who sought the Nile’s origins.

The Weizmann scientists, led by Karina Yaniv, Ph.D., gave an account of their work May 20 in Nature, where they described the lay of the land as follows: “Multipotent progenitors undergo cell-fate restriction in response to cues from the microenvironment, the nature of which is poorly understood.”

Undaunted, Dr. Yaniv and colleagues not only determined the source of lymphatic cells, they used their newfound knowledge to grow, for the first time, lymphatic cells in the laboratory. As for the source, that is made clear in the title of their Nature paper: “Lymphatic vessels arise from specialized angioblasts within a venous niche.”

“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,” the article’s authors wrote. “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.”

When Weizman postdoctoral fellow Yogev Sela added WNT5B to human embryonic stem cells, these cells indeed differentiated into lymphatic cells—the first time such cells had been grown in the lab. “We started out by imaging zebrafish, and ended up finding a factor that makes it possible to create lymphatic cells,” said Dr. Yaniv. “That's the beauty of research in developmental biology: The embryo holds the answers, and all we have to do is watch and learn.”

Aside from the feat of answering the longstanding question of how the lymph system arises, understanding how it forms and develops can provide important insights into disease, from metastasis to the abnormal accumulation of lymph fluids, particularly in the wake of surgery to remove cancerous tumors.








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