Lymphatic vessels play crucial roles during embryogenesis and in adult animals but the origin of their progenitor cells is controversial. Recent studies have suggested that during neo-lymphangiogenesis in inflammatory settings, macrophages transdifferentiate into lymphatic endothelial cells and/or release pro-lymphangiogenic growth factors, but are these mechanisms involved in the development of the normal lymphatic vasculature? On p. 3899, Natasha Harvey and co-workers suggest that the answer to this question is no. Using lineage tracing, the researchers show that lymphatic endothelial cells arise independently of the myeloid lineage during both embryogenesis and tumour-stimulated lymphangiogenesis in the mouse. Thus, they suggest, macrophages are not the source of lymphatic endothelial progenitor cells in these settings. Furthermore, the dermal lymphatic vasculature in macrophage-deficient mice is hyperplastic because of increased lymphatic endothelial cell proliferation. So, rather than providing pro-lymphangiogenic growth factors, macrophages provide signals that restrain lymphatic endothelial cell proliferation. Given these results, any attempt to treat disease-stimulated lymphangiogenesis by targeting macrophages needs careful consideration, conclude the researchers.

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