Inducible human yolk sac myeloid progenitors model myeloid ontogeny and enable tissue-resident macrophage replacement in vivo.

Tissue-resident macrophages (TRMs) are involved in the surveillance and maintenance of tissue homeostasis, yet their dysfunction is a hallmark of human diseases. Although mouse TRMs arise from sequential migrations of yolk sac progenitors, limited access to human embryonic tissue has hindered the study of the origin of human TRMs. Here, we develop an in vitro system that generates inducible yolk sac myeloid progenitors (iYSMPs) to model human myeloid ontogeny. iYSMPs share the transcriptomic profile of yolk sac progenitors from human embryos and differentiate into macrophages, granulocytes, and erythroid lineages in vitro, mimicking human ontogeny. Upon systemic xenotransplantation, iYSMPs acquire organ-specific TRM identities and differentiate into microglia, border-associated macrophages, Kupffer cells, and cardiac and renal macrophages. These findings define a human yolk sac progenitor state with broad TRM differentiation potential, opening avenues for investigating human myeloid ontogeny and developing macrophage cell replacement therapies to treat human diseases.