Lymphangioblasts in Embryonic Lymphangiogenesis

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Abstract
Background: The origin of the lymphatic endothelium, either from the venous system or mesenchymal lymphangioblasts, presents as a persistent controversy. Recently, highly specific markers of the lymphatic endothelium have been found, enabling us to reinvestigate the embryonic origin of the lymphatics. Methods and Results: The homeobox transcription factor, Prox1, is expressed in lymphatic, but not in blood vascular, endothelial cells throughout murine and avian development and in adult human tissues. Here we show expression of scattered Prox1-positive cells in the dermatome of 4-day-old chick embryos by in situ hybridization and immunostaining. These cells obviously form the Prox1-positive lymphatic networks in the skin of the body wall and the limbs during further embryonic development. The Prox1 protein is localized in the nuclei of the lymphatic endothelial cells (LECs). Conclusions: The results strongly suggest that the superficial lymphatics develop independently from the deep ones, and are derived from mesenchymal lymphangioblasts rather than veins. Our results argue against the unique origin of lymphatics from veins and suggest a heterogenous origin of LECs. The results are discussed in the context of historical data.