![]() Recent studies using genetic lineage tracing confirmed Sabin’s hypothesis that lymphatic vessels originate from the embryonic cardinal vein through lymphangiogenesis ( Srinivasan et al., 2007 Yang et al., 2012). The origin of lymphatic endothelial cells (LECs) has been discussed since the 1900s ( Huntington and McClure, 1910 Sabin, 1902). ![]() ![]() Furthermore, recent progress in molecular and cellular characterization has unveiled the processes involved in the development of the lymphatic vasculature and the roles played by the lymphatic vasculature in various pathophysiological conditions ( Klaourakis et al., 2021 Maruyama et al., 2021 Maruyama and Imanaka-Yoshida, 2022 Oliver et al., 2020 Oliver and Alitalo, 2005). The lymphatic vascular system plays diverse roles in the maintenance of tissue fluid balance, immune surveillance, lipid absorption from the gut, and tumor metastasis ( Oliver and Alitalo, 2005). Most importantly, our findings may provide clues to the pathogenesis of lymphatic malformations, which most often develop in the craniofacial and mediastinal regions. As the CPM is evolutionarily conserved, these findings may improve our understanding of the evolution of lymphatic vessel development across species. Collectively, our results demonstrate that there are two major sources of LECs, the cardinal vein and the CPM. Later, they form the craniofacial and cardiac lymphatic vascular networks in collaboration with venous-derived LECs. ![]() These CPM-derived LECs are distinct from venous-derived LECs in terms of their developmental processes and anatomical locations. Genetic lineage tracing with Isl1 Cre/+ and Isl1 CreERT2/+ mice suggested that a subset of CPM cells gives rise to LECs. Here, we identify the Islet1 ( Isl1)-expressing cardiopharyngeal mesoderm (CPM) as a non-venous origin of craniofacial and cardiac LECs. However, the contribution of LECs from non-venous origins to lymphatic networks is considered to be relatively small. Recent studies have demonstrated that lymphatic endothelial cells (LECs) arise from both venous sprouting (lymphangiogenesis) and de novo production from non-venous origins (lymphvasculogenesis), which is similar to blood vessel formation through angiogenesis and vasculogenesis. ![]() Lymphatic vessels are crucial for tissue homeostasis and immune responses in vertebrates. ![]()
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