In a recent model of adult pathological neo-lymphangiogenesis, macrophages were suggested to contribute to the genesis of lymphatic vessels through a process of `transdifferentiation' to lymphatic endothelial cells ( Kerjaschki et al., 2006 Maruyama et al., 2005). Likewise, whether postnatal lymphatic vascular growth and development in response to inflammatory stimuli, including the tumour microenvironment (neo-lymphangiogenesis), occurs by sprouting from existing lymphatic vessels or via a contribution from circulating progenitor cells, is not well established. The mechanism of embryonic lymphatic vascular growth following progenitor cell specification remains poorly defined it is not clear whether lymphatic vessels grow solely via the continuous sprouting and proliferation of established lymphatic endothelial cells, or whether an additional source of progenitor cells contributes to their growth and development. Recent molecular evidence has demonstrated that, in mouse, at least a substantial proportion of lymphatic endothelial cells arises from venous progenitors following the induction of expression of the homeobox transcription factor, PROX1 ( Srinivasan et al., 2007 Wigle and Oliver, 1999). Two schools of thought have been actively debated the first proposes that lymphatic endothelial progenitors arise from the embryonic veins, the second proposes a dual origin from venous and mesenchymal components ( Oliver, 2004). The embryonic origin of lymphatic endothelial progenitor cells has long been a controversial topic in lymphangiogenesis research. In contrast to what has been demonstrated in settings of inflammation, macrophages do not comprise the principal source of pro-lymphangiogenic growth factors, including VEGFC and VEGFD, in the embryonic dermal microenvironment, illustrating that the sources of patterning and proliferative signals driving embryonic and disease-stimulated lymphangiogenesis are likely to be distinct. In addition, we demonstrate that the dermal lymphatic vasculature of PU.1 –/– and Csf1r –/– macrophage-deficient mouse embryos is hyperplastic owing to elevated lymphatic endothelial cell proliferation, suggesting that cells of the myeloid lineage provide signals that act to restrain lymphatic vessel calibre in the skin during development. ![]() Here, we provide lineage tracing evidence to demonstrate that lymphatic endothelial cells arise independently of the myeloid lineage during both embryogenesis and tumour-stimulated lymphangiogenesis in the mouse, thus excluding macrophages as a source of lymphatic endothelial progenitor cells in these settings. We set out to establish whether cells of the myeloid lineage are important for development of the lymphatic vasculature through either of these mechanisms. Macrophages have been suggested to stimulate neo-lymphangiogenesis in settings of inflammation via two potential mechanisms: (1) acting as a source of lymphatic endothelial progenitor cells via the ability to transdifferentiate into lymphatic endothelial cells and be incorporated into growing lymphatic vessels and (2) providing a crucial source of pro-lymphangiogenic growth factors and proteases.
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