The maternal–fetal interface is an early hematopoietic niche enriched in distinct erythro-myeloid progenitors

Embryonic hematopoiesis is thought to occur exclusively in the extraembryonic yolk sac before hematopoietic stem cells (HSCs) arise in the aorta–gonad–mesonephros region. Here we identify a previously unrecognized hematopoietic site at the maternal–fetal interface in mice, termed MIXER (Maternally Interfaced eXtraEmbRyonic) tissue, which develops contemporaneously with the yolk sac and exhibits robust hematopoietic activity. MIXER contains abundant hematopoietic precursors, including classical CSF1R + erythro-myeloid progenitors and a unique embryonic CD4 + CSF1R − Erythro-Myeloid PRogenitOR (eEMPROR) population. Lineage-tracing experiments demonstrate that eEMPROR cells contribute to select macrophage subpopulations during fetal development, primarily in the perivascular space. Notably, early human placental villi, before HSC emergence, also harbor CD4 + nucleated erythrocytes, indicating a conserved hematopoietic role for the maternal–fetal interface. These findings establish MIXER as an anatomically distinct niche for embryonic hematopoiesis and expand the developmental map of blood cell emergence in mammals.