Cardiac lymphatics are heterogeneous in origin and respond to injury

The lymphatic vasculature is a blind-ended network crucial for tissue-fluid homeostasis, immune surveillance and lipid absorption from the gut. Recent evidence has proposed an entirely venous-derived mammalian lymphatic system. By contrast, here we show that cardiac lymphatic vessels in mice have a heterogeneous cellular origin, whereby formation of at least part of the cardiac lymphatic network is independent of sprouting from veins. Multiple Cre–lox-based lineage tracing revealed a potential contribution from the putative haemogenic endothelium during development, and discrete lymphatic endothelial progenitor populations were confirmed by conditional knockout of Prox1 in Tie2+ and Vav1+ compartments. In the adult heart, myocardial infarction promoted a significant lymphangiogenic response, which was augmented by treatment with VEGF-C, resulting in improved cardiac function. These data prompt the re-evaluation of a century-long debate on the origin of lymphatic vessels and suggest that lymphangiogenesis may represent a therapeutic target to promote cardiac repair following injury. The lymphatic system is thought to be derived by transdifferentiation of venous endothelium; this study shows that the origin of cardiac lymphatics is in fact more heterogeneous, including both venous and non-venous origins and that lymphangiogenesis occurs in the adult heart following myocardial infarction and can be enhanced to improve heart function. The lymphatic endothelium wass thought to arise entirely from transdifferentiation of the venous endothelium. Two studies published in this issue of Nature demonstrate that the origins of this vasculature are more varied than anticipated. Karina Yaniv and colleagues use live imaging of transgenic zebrafish embryos to trace the lineage of individual lymphatic endothelial cells and their progeny. They find that lymphatic progenitors emerge from a previously uncharacterized pool of multipotent angioblasts located in the floor of the cardinal vein, which bears the potential to generate not only lymphatic, but also arterial and venous fates. Paul Riley and colleagues used genetic fate-mapping techniques in mice to demonstrate a dual origin of cardiac lymphatic endothelial cells, involving both venous endothelium and a separate non-venous progenitor source arising from yolk sac cells. They also show that the lymphangiogenesis in the heart can be influenced by myocardial infarction, and they suggest that promoting lymphangiogenesis with VEGF-C improves cardiac function after infarction