Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/78330
Type: Thesis
Title: Defining the role of myeloid cells in the regulation of developmental, tumour and inflammation-stimulated lymphangiogenesis.
Author: Gordon, Emma Joan
Issue Date: 2011
School/Discipline: School of Medicine
Abstract: Lymphatic vessels are an integral component of the cardiovascular system. These specialised vessels are essential for the return of interstitial fluid to the bloodstream, immune cell trafficking and the absorption of fats from the digestive tract. Despite the crucial role played by lymphatic vessels in homeostasis and human disease, little is known about the signals that regulate lymphatic vascular growth and development (lymphangiogenesis). The aim of this project was to investigate the role of two lineages of immune cells, macrophages and mast cells, in embryonic, tumour and inflammation-stimulated lymphangiogenesis. The first aim of this study was to determine the expression pattern of LYVE-1, a marker expressed on lymphatic vessels and a sub-population of macrophages, during early embryonic development. LYVE-1 expression was documented for the first time in the yolk sac blood vasculature and in early embryonic arteries, inter-somitic veins and endothelial cells of the lung and endocardium. These results have important implications for the use of LYVE-1 as a specific marker of lymphatic vascular endothelium. The major aim of this project was to investigate the role of cells of the macrophage lineage in lymphangiogenesis. Macrophages expressing LYVE-1 were intimately associated with developing lymphatic vessels in the mouse embryo. Characterisation of this sub-population of LYVE-1-positive macrophages revealed that they shared a gene expression profile with Tie2-expressing monocytes. Lineage tracing studies illustrated that, while localised in close association with lymphatic vessels, macrophages did not trans-differentiate to lymphatic endothelial cells during embryonic or tumour-stimulated lymphangiogenesis. These data provide strong support to exclude myeloid cells as a source of lymphatic endothelial progenitor cells. Characterisation of lymphatic vascular development in macrophage deficient mice revealed that macrophages play a key role in shaping the dermal lymphatic vasculature during development by regulating lymphatic endothelial cell proliferation. The final aim of this study was to investigate the role of mast cells during embryonic and inflammation-stimulated lymphangiogenesis. While mast cells appeared to be dispensable for the construction of the lymphatic vasculature, they were found to play a key role in UVB irradiation-induced lymphangiogenesis. Hyperplastic lymphatic vessels were a striking feature of UVB irradiated tissue in mast cell-deficient mice, revealing a novel role for mast cells in restraining the magnitude of lymphangiogenesis stimulated by this inflammatory insult. In conclusion, these studies provide strong evidence to exclude cells of the myeloid/macrophage lineage as a pool of lymphatic endothelial progenitor cells during development and in the tumour microenvironment. This work has discovered that macrophages define the calibre of dermal lymphatic vessels during development by restraining lymphatic endothelial cell proliferation. This is in contrast to previous studies which reported macrophages stimulate lymphangiogenesis in settings of inflammation. In addition, a previously undescribed role for mast cells in the regulation of inflammation-stimulated lymphangiogenesis was identified. Taken together, these data illustrate that the sources of signals driving embryonic and disease-stimulated lymphangiogenesis are likely to be distinct. As myeloid cells regulate lymphangiogenesis in disease states, the results of this project have important implications when considering the targeting of myeloid cells for lymphangiogenic therapies.
Advisor: Harvey, Natasha Lynn
Kumar, Sharad
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2011
Keywords: lymphangiogenesis; macrophage; myeloid cells; development; inflammation
Appears in Collections:Research Theses

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