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Most haematopoietic cells renew from adult hematopoietic stem cells (HSC) 1–3, however, macrophages in adult tissues can self-maintain independently of HSC4–7. Progenitors with macrophage potential in vitro have been described in the yolk sac before emergence of HSC8–13, and fetal macrophages13–15 can develop independently of Myb4, a transcription factor required for HSC16, and can persist in adult tissues4, 17, 18. Nevertheless, the origin of adult macrophages and the qualitative and quantitative contributions of HSC and putative non-HSC progenitors are still unclear19. Here we show that the vast majority of adult tissueresident macrophages in liver (Kupffer cells), brain (microglia), epidermis (Langerhans cells), and lung (alveolar macrophages) originate from a Tie2+ cellular pathway generating Csf1r+ erythro-myeloid progenitors (EMP) distinct from HSC. EMP develop in the yolk sac at embryonic …