Abstract
Tissue macrophages in many adult organs originate from yolk sac (YS) progenitors, which invade the developing embryo and persist by means of local self-renewal. However, the route and characteristics of YS macrophage trafficking during embryogenesis are incompletely understood. Here we show the early migration dynamics of YS-derived macrophage progenitors in vivo using fate mapping and intravital microscopy. From embryonic day 8.5 (E8.5) CX3CR1+ pre-macrophages are present in the mouse YS where they rapidly proliferate and gain access to the bloodstream to migrate towards the embryo. Trafficking of pre-macrophages and their progenitors from the YS to tissues peaks around E10.5, dramatically decreases towards E12.5 and is no longer evident from E14.5 onwards. Thus, YS progenitors use the vascular system during a restricted time window of embryogenesis to invade the growing fetus. These findings close an important gap in our understanding of the development of the innate immune system.
Highlights
Macrophages are important effectors of innate immunity
Green fluorescent protein (GFP)-labeling in Cx3cr1GFP/+ embryos corresponds to the CX3CR1+ CD45+ c-KIT- (“A3-like”) population previously characterized in vitro, while other hematopoietic lineages are not labeled (Supplementary Fig. 1a–c)[8,12]
In parallel to the increase in cell numbers, CX3CR1+ premacrophages underwent morphological changes from spherical shape to mature cells with multiple dendrites (Fig. 1d) potentially engaging in direct cell-to-cell contacts, as it is typically found in adult tissues[24]
Summary
Macrophages are important effectors of innate immunity. They have a critical function in organ development, maintenance of tissue homeostasis and host protection during infection[1]. Fate mapping analyses and lineage tracing experiments have indicated that tissue macrophages in many organs are of early embryonic origin[7,8,9,10,11]. Monocytes and other short-lived myeloid cells are continuously replaced, whereas tissue macrophages can self-renew and persist independently of definitive BM hematopoiesis for prolonged periods of time, potentially throughout life[8,16,20]. Even though macrophage trafficking during early embryonic development is a prerequisite for establishing this important component of the innate immune system, the kinetics of this process have not been defined. Tissue resident macrophages addithese markers allow genetic labeling and visualization of macrophage progenitors early during embryonic development
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