Earliest step of lymphatic system formation discovered

Lymphatic endothelium has same embryonic origin as skeletal muscle

The innermost layer of lymphatic and blood vessels consists of endothelial cells. These are essential for vessels to function. So far it has been assumed that in the course of embryonic development, specialization of endothelial cells is controlled by the tissue surrounding them.  Scientists from the Max Planck Institute for Heart and Lung Research in Bad Nauheim have now discovered that the differentiation of endothelial cells in the lymphatic vessels takes place much earlier. The cells originate from the areas of the mesoderm from which the musculature also develops. Because the lymphatic system is involved in many diseases, the study of Bad Nauheim scientists could also have a significance for future therapies.

The human body contains two different vascular systems, namely the blood vasculature and the lymphatic system. Although blood and lymphatic vessels are closely related, they have quite different tasks. The lymphatic vessels are of major importance for the immune system, as they, among other things, channel lymphocytes through the body. The lymphatic vessels are also important for fluid transportation. In addition, tumor cells often spread via the lymphatic system into other areas of the body.

Oliver Stone, a former scientist from the "Developmental Genetics" department led by Didier Stainier, at the Max Planck Institute for Heart and Lung Research in Bad Nauheim, has now deciphered the origins of the lymphatic system during embryonic development. "So far, it has been assumed that formation of lymphatic vessels occurs only at a relatively late stage of embryonic development, after the formation of arteries and veins" said Stainier. "In contrast, we were now able to show for the first time that the origin of the lymphatic vessels is determined at a much earlier stage of development." 

Endothelial cells from the paraxial mesoderm

"Endothelial cells, as well as blood and the muscle of the heart, originate in an area of the embryo called mesoderm. In response to signals from the surrounding tissue, mesodermal cells mature to form these specialized cell types" said Stainier. In their study, the Max Planck researchers used genetically modified mice to observe the behavior of specific mesodermal cells during embryonic development. Using this strategy, they could identify the origin of lymphatic endothelial cells: "The endothelial cells of most lymphatic vessels derive from a limited part of the mesoderm, the so-called paraxial mesoderm. It’s from this area of the embryo that skeletal muscle, tendons and cartilage also arise" said Stone. Furthermore, the Bad Nauheim scientists showed that only very few blood vessels had their origin in this area, a clear indication that blood and lymph vessels are of different origin. 

To confirm this finding, the researchers knocked out a gene which is responsible for the formation of lymphatic endothelial cells specifically in the cells of the paraxial mesoderm. In mice in which the gene called Prox1 was switched off in these cells, the development of the lymphatic system was severely disturbed and impaired its function. "Our study shows that the unique traits of endothelial cells in different vascular beds may be fixed very early during embryonic development," said Stone. In further studies, Stone wants to understand whether different types of endothelial cells react differently to disease. "If this were due to their different origins in the embryo, it could significantly impact the way in which cardiovascular disease is treated in the future," concludes Stone.

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