Fate Mapping via Ms4a3-Expression History Traces Monocyte-Derived Cells

Most tissue-resident macrophage (RTM) populations are seeded by waves of embryonic hematopoiesis and are self-maintained independently of a bone marrow contribution during adulthood. A proportion of RTMs, however, is constantly replaced by blood monocytes, and their functions compared to embryonic RTMs remain unclear. The kinetics and extent of the contribution of circulating monocytes to RTM replacement during homeostasis, inflammation, and disease are highly debated. Here, we identified Ms4a3 as a specific gene expressed by granulocyte-monocyte progenitors (GMPs) and subsequently generated Ms4a3TdT reporter, Ms4a3Cre, and Ms4a3CreERT2 fate-mapping models. These models traced efficiently monocytes and granulocytes, but no lymphocytes or tissue dendritic cells. Using these models, we precisely quantified the contribution of monocytes to the RTM pool during homeostasis and inflammation. The unambiguous identification of monocyte-derived cells will permit future studies of their function under any condition. [Display omitted] •Ms4a3 is specifically and transiently expressed by GMPs in the bone marrow•MDPs do not arise from GMPs and do not give rise to cMoPs•Ms4a3-based models specifically and efficiently fate map monocytes and granulocytes•Distinguish monocyte- versus embryonic-derived RTMs in steady state and inflammation A fate-mapping model provides insights into the ontogeny of specific monocyte populations and their contributions to the tissue-resident macrophage pools during homeostasis and inflammation.