Endothelial progenitor cells / Wnt5a in lymphangiogenesis
Endothelial progenitor cells
As noted above, there is evidence that, also in man, progenitor cells contribute to the development of the lymphatic vascular system. To identify such progenitor cells, we characterize circulating endothelial progenitor cells (EPCs), which are present in peripheral blood of children and infants. The endothelial character of such cells has been analysed by a number of labs. However, it has remained unknown if there are circulating lymphendothelial progenitor cells among these EPCs. There seems to be clinical use for such cells in regenerative medicine for the treatment of various lymphangiodysplasias. To study the use of such cells experimentally, we started a collaboration with Dr. H.A. Weich (Helmholtz Zentrum für Infektionsforschung, Braunschweig). We isolate endothelial progenitor cells from mice, characterize them and study their behaviour after transplantation into nude mice. Thereby we induce lymphangiogenesis through inflammatory stimuli, by intraperitoneal injection of Freund’s Incomplete Adjuvant (FIA), a mineral oil, which induces non-specific inflammatory mechanisms. In future studies we will use human endothelial progenitor cells in nude mice.
Wnt5a in lymphangiogenesis
Molecular comparison of human vein endothelial cells (HUVECs) and lymphatic endothelial cells (LECs) revealed many differentially expressed genes between these two cell types. Besides well-known LEC markers, we observed regulation of WNT pathway components, which play important roles in embryonic development. They control fundamental mechanisms during morphogenesis of various organs via proliferation, migration, polarization and cell fate specification. WNTs belong to a family of secreted glycoproteins that operate via three pathways with several receptors and co-receptors. Dysregulation of WNT signaling pathways has been observed in pathological conditions, e.g. in cancer, rheumatoid arthritis and Alzheimer’s disease. One of the family members, WNT5A, is highly expressed in LECs. Although, WNT5A has been regarded as a regulator of angiogenesis, its role in lymphangiogenesis has not been addressed by now. Our recent studies support a role for WNT5A in the morphogenesis of lymphatic networks. Wnt5a-knock-out mouse embryos possess significantly fewer but larger dermal lymphatic capillaries as compared to the controls, and lack functional lymphatic collectors. We now study the cellular and molecular mechanisms by which WNT5A controls the morphogenesis of embryonic lymphatic vessels.