Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors

Most haematopoietic cells renew from adult haematopoietic stem cells (HSCs)(1-3), however, macrophages in adult tissues can self-maintain independently of HSCO4-7. Progenitors with macrophage potential in vitro have been described in the yolk sac before emergence of HSCO8-3, and fetal macrophages(13-15) can develop independently of Myb(4), a transcription factor required for HSC16, and can persist in adult tissues(4.17,18). Nevertheless, the origin of adult macrophages and the qualitative and quantitative contributions of HSC and putative non-HSC-derived progenitors are still unclear'. Here we show in mice that the vast majority of adult tissue-resident macrophages in liver (Kupffer cells), brain '(microglia), epidermis (Langerhans cells) and lung (alveolar macrophages) originate from a Tie2(+) (also known as Tek) cellular pathway generating Csf1r(+) erythro-myeloid progenitors (EMPs) distinct from HSCs. EMPs develop in the yolk sac at embryonic day (E) 8.5, migrate and colonize the nascent fetal liver before E10.5, and give rise to fetal erythrocytes, macrophages, granulocytes and monocytes until at least E16.5. Subsequently, HSC-derived cells replace erythrocytes, granulocytes and monocytes. Kupffer cells, microglia and Langerhans cells are only marginally replaced in oneyear-old mice, whereas alveolar macrophages may be progressively replaced in ageing mice. Our fate-mapping experiments identify, in the fetal liver, a sequence of yolk sac EMP-derived and HSC-derived haematopoiesis, and identify yolk sac EMPs as a common origin for tissue macrophages.