Tissue-resident macrophages have been implicated in the organogenesis and regeneration of several organs. However, the origin and function of organ-specific macrophages is not clear. Now, Paul Riley and colleagues ascertain the contribution of mouse cardiac macrophages during cardiac lymphatic development. Using a combination of techniques to profile the temporal-spatial distribution of macrophages in the developing heart, the authors show that macrophages first colonise the heart at around E10.5 before cardiac lymphatics begin to form. From E12.5, during the onset of cardiac lymphangiogenesis, macrophages are located proximal to and in contact with the growing lymphatic vessels. The researchers employ inducible genetic models to label populations from the extra-embryonic yolk sac or intra-embryonic haematopoietic stem cells of the foetal liver, to show that macrophages associated with the developing lymphatics are largely derived from the yolk sac. Furthermore, genetic deletion of this specific macrophage population disrupts lymphatic growth and patterning, shown by shorter lymphatic vessels and fewer junctions. By modelling lymphatic growth in vitro, they identify that lymphatic endothelial cells sprout in response to hyaluronan produced by macrophages. Together, these data show that yolk-sac derived cardiac macrophages regulate cardiac lymphatic development through hyaluronan and further support macrophages as a potential therapeutic target for cardiovascular disease and injury.
