Mechanical cue for lymphatic vessel formation
In a study from IGP the researchers show for the first time how the formation of the body’s lymphatic vasculature is affected by the stiffness of the substance that surrounds the first cells forming the new vessels. The results that are published today in the journal Nature Communications can explain the mechanism behind a genetic lymphatic vessel disease and suggest new ways to control such conditions.
All cells in our body are exposed to many different types of mechanical forces, such as stretching, pulling and compression, which have been increasingly recognized as key regulators of cell behavior and fate during development and disease. Another force that affects the cells is the stiffness of the substance in which the cells are embedded. This substance is called the extracellular matrix and consists of polysaccharides, protein fibers and fluid. In the present study the researchers have discovered that the stiffness of the matrix plays a critical role in regulating cell behavior when the first lymphatic vessels are formed.
“During embryo development lymphatic vessels are formed when endothelial cells. i.e. the cells that line the vessel walls, migrate out from the previously formed veins to the surrounding tissue to form the first lymphatic vessels. There they are exposed to a dramatic decrease in matrix stiffness and we found that this induces a specific gene in the endothelial cells, which in turn controls the continued early lymphatic vascular development,” says Maike Frye, post doctoral researcher at IGP and first author of the study.
The gene that was activated by the softer matrix is called GATA2. It encodes a protein that regulates a number of other genes involved in controlling cell migration. Thus, the study suggests a new signaling pathway where matrix stiffness regulates GATA2 activation, endothelial cell migration and lymphatic vessel development. It could explain how lymphatic vascular failure is caused by mutations in GATA2 in the hereditary lymphedema disease Emberger syndrome.
“It is also interesting to note that chronic lymphedema, where tissues swell because the lymphatic vessels fail to drain them of excess fluid, is accompanied by tissue stiffening. Our results thus further suggest that targeting tissue stiffness may be important for controlling disease progression and therapy response in these diseases,” says Taija Mäkinen, who has led the study.
The study was performed in collaboration with researchers at KTH in Stockholm and in the UK, Finland Germany and China.