Cahill, Thomas JSun, XinRavaud, ChristopheVilla del Campo, CristinaKlaourakis, KonstantinosLupu, Irina-ElenaLord, Allegra MBrowne, CathyJacobsen, Sten Eirik WGreaves, David RJackson, David GCowley, Sally AJames, WilliamChoudhury, Robin PVieira, Joaquim MiguelRiley, Paul R2021-08-252021-08-252021-01Development. 2021; 148(3):dev.1945630950-1991http://hdl.handle.net/20.500.12105/13308Macrophages are components of the innate immune system with key roles in tissue inflammation and repair. It is now evident that macrophages also support organogenesis, but few studies have characterized their identity, ontogeny and function during heart development. Here, we show that the distribution and prevalence of resident macrophages in the subepicardial compartment of the developing heart coincides with the emergence of new lymphatics, and that macrophages interact closely with the nascent lymphatic capillaries. Consequently, global macrophage deficiency led to extensive vessel disruption, with mutant hearts exhibiting shortened and mis-patterned lymphatics. The origin of cardiac macrophages was linked to the yolk sac and foetal liver. Moreover, the Cx3cr1 + myeloid lineage was found to play essential functions in the remodelling of the lymphatic endothelium. Mechanistically, macrophage hyaluronan was required for lymphatic sprouting by mediating direct macrophage-lymphatic endothelial cell interactions. Together, these findings reveal insight into the role of macrophages as indispensable mediators of lymphatic growth during the development of the mammalian cardiac vasculature.engVoRLymphatic VesselsAnimalsCX3C Chemokine Receptor 1Cell AdhesionCell LineEndothelial CellsGene Expression Regulation, DevelopmentalGene Knock-In TechniquesHeartHumansInflammationLymphangiogenesisMacrophagesMiceMice, Inbred C57BLOrganogenesisReceptors, Granulocyte-Macrophage Colony-Stimulating FactorYolk SacAtribución 4.0 Internacional33462113148310.1242/dev.1945631477-9129Development (Cambridge, England)open access