Scientists have broken new ground in understanding how the lymphatic system works, potentially opening the door for future therapies.
The lymphatic system is a network of vessels and lymph nodes that spans the entire body. It is critical for good health and for the body to function properly. Defects in lymphatic vessels cause lymphedema, a disease characterized by dramatic and painful swelling in the limbs that often leads to infections. Lymphedema can result from congenital mutations, surgery, radiation treatment for cancer or infection, and there is currently no cure. In addition to lymphedema, defects in the lymphatic system have been linked to a wide range of health consequences: cancer, atherosclerosis, Alzheimer's disease and obesity.
Researchers previously discovered that a particular pathway--known as the Wnt signaling pathway--regulates the development of the human lymphatic vascular system. In new research, published in the journal Cell Reports, they've found "the nuts and bolts of this important pathway."
Authors show that oscillatory shear stress activates autocrine Wnt/β-catenin signaling in LECs (lymphatic endothelial cells) in vitro. Tissue-specific deletion of Wntless, which is required for the secretion of Wnt ligands, reveals that LECs and vascular smooth muscle cells are complementary sources of Wnt ligands that regulate lymphatic vascular development in vivo.
Further, the LEC master transcription factor PROX1 forms a complex with β-catenin and the TCF/LEF transcription factor TCF7L1 to enhance Wnt/β-catenin signaling and promote FOXC2 and GATA2 expression in LECs.
"We have identified the signaling molecules that activate this pathway," said the senior author. "We also have learned which cells produce the signaling molecules, how they are sensed by the cells and how they are used in lymphatic development."
"This signaling pathway has proved difficult to study, because it is complex and so little is known about how it functions normally, let alone when it goes wrong," said the senior author. "Wnt signaling is aggravated and increased in breast cancer and colon cancer, but it is deregulated in diseases like Alzheimer's and lymphedema.".
The lymphatic vascular system development dissected!
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