Editors' ChoiceDevelopment

Lymph Vessel Sites Defined by Monocytes

Science Signaling  23 Mar 2010:
Vol. 3, Issue 114, pp. ec85
DOI: 10.1126/scisignal.3114ec85

Lymphatic vessels are important for immune responses and resorption of dietary fats and, although close to the blood circulatory vessels, form a completely separate system with only two exceptions where the lymphatic system connects to the venous circulatory system. In adult mice, myeloid cells are sources of the lymphangiogenic growth factors, vascular endothelial growth factors C and D (VEGF-C, VEGF-D), but the role that myeloid cells play in the embryonic development of the lymphatic system is unknown. Knockout of the receptor tyrosine kinase Syk is embryonic lethal in mice due to extensive blood vessel–lymphatic malformations and lack of proper separation. Böhmer et al. examined in detail the morphological defects of the Syk–/– embryos and found lymphatic hyperplasia resulting in extensive contact between blood vessel endothelial cells and lymphatic endothelial cells (LECs). With genetic tracing (introduction of a reporter controlled by the Syk promoter), the authors determined that Syk was not expressed by the LECs but instead was present in cells characterized by marker analysis and morphology as predominantly a specific type of monocyte, M2 monocytes. The abundance of these monocytes was increased in the skin of Syk–/– mouse embryos, and these Syk–/– skin monocytes stimulated mouse endothelial cell sprouting in vitro. Skin monocytes from the Syk–/– mice exhibited enhanced transcript abundance for multiple angiogenic growth factors, including VEGF-D. Both wild-type and Syk–/– skin monocytes exhibited lymphangiogenic activity in a skin transplant model, with the knockout cells stimulating more branch sprouting at lower cell densities. The lymphangiogenic properties of both wild-type and knockout cells were blocked by inhibiting VEGF-C and VEGF-D activity. Thus, during development, myeloid cells in the skin release angiogenic factors that stimulate lymphogenesis, and loss of Syk results in enhanced production of these factors, causing lymphatic endothelial cell overgrowth.

R. Böhmer, B. Neuhaus, S. Bühren, D. Zhang, M. Stehling, B. Böck, F. Kiefer, Regulation of developmental lymphangiogenesis by Syk+ leukocytes. Dev. Cell 18, 437–449 (2010). [PubMed]