The contribution of fetal macrophages, relative to that of macrophages derived from hematopoietic stem cells (HSCs), to adult tissues remains unclear. In Nature, Rodewald, Geissmann and colleagues show that most adult tissue macrophages originate from yolk sack–derived erythro-myeloid progenitors (EMPs) that are distinct from HSCs. Tracing of fetal and adult HSCs with the marker Flt3 shows that only 14% of liver Kupffer cells, 2% of brain microglia, 30% of epidermal Langerhans cells and 40% of lung alveolar macrophage are HSC derived in 1-year-old mice. Pulse labeling for expression of the endothelial cell receptor Tie2 shows that yolk sack–derived EMPs generate all fetal tissue macrophages up to embryonic day 15.5 of mouse development and also contribute to 30–60% of tissue-resident macrophages in adult mice. Yolk sack–derived macrophages are replaced by HSC-derived cells only marginally in the brain, liver and epidermis of adult mice at steady state. Populations of yolk sack–derived EMPs expand in the fetal liver, where they overlap with Flt3+ HSC-derived progenitors; this suggests caution should be taken in the interpretation of experiments using fetal liver progenitor cells.

Nature (3 December 2014) doi:10.1038/nature13989