Blood originates in hypoblasts during embryonic development

Blood is essential for oxygen supply throughout life. The emergence of blood in the human embryo remains poorly understood. Our study leverages multiple stem cell embryo models and advanced lineage barcoding to unveil that hypoblast, originally regarded as forming the yolk sac wall, is heterogeneous and contributes to CDX2+ extraembryonic mesoderm, followed by hemoglobin+ cells as the first blood cells. CDX2 marks the hypoblast-to-hemoglobin+ cell trajectory that functionally sustains oxygen levels in embryo models. These hemoglobin+ cells molecularly and functionally resemble phagocytes. We show that the erythro-core regulatory network is poised in hypoblasts, and its boost endows erythropoiesis to both hypoblasts and phagocytes. Hypoblasts are the origin of the first blood in humans and non-human primates, providing a conceptual framework that earlier blood generation than expected fills the gap in the establishment of circulation. Further, the hypoblast is a place where primates may repurpose the phagocyte program to carry oxygen throughout embryos. HighlightsO_LIBarcode-traced hypoblast fate in human embryo models; C_LIO_LIThe first blood comes from the hypoblast that contributes to hemoglobin+ phagocyte-like cells; C_LIO_LICDX2 marks hypoblast blood that sustains oxygen supply in embryos before heart formation; C_LIO_LIErythro-core regulatory network endows erythropoiesis to human hypoblasts and phagocytes. C_LI