Integrative cross-species transcriptome analysis reveals earlier occurrence of myelopoiesis in pre-circulation...

Hematopoiesis originates in the yolk sac, which forms prior to the establishment of blood circulation and exhibits distinct developmental processes between primates and mice. Despite increasing appreciation of yolk sac hematopoiesis for its lifelong contribution to the adult hematopoietic system and its regulatory roles in organogenesis, cross-species differences, particularly before the onset of blood circulation, remain incompletely understood. In this study, we constructed an integrative cross-species transcriptome atlas of pre-circulation hematopoiesis in humans, monkeys ( Macaca fascicularis), and mice. This analysis identified conserved populations between primates and mice, while also revealing more differentiated myeloid, erythroid, and megakaryocytic lineages in pre-circulation primates compared to mice. Specifically, SPP1-expressing macrophages were detected in primates before the onset of blood circulation but were absent in mice. Cell-cell communication analysis identified CSF1 ⁺ extraembryonic mesoderm cells as a potential supportive niche for macrophage generation, with ligand-receptor interactions between macrophages and other cell populations in the human yolk sac. Interestingly, pre-circulation SPP1 macrophages exhibited hallmark signatures reminiscent of a macrophage subset that positively regulates hematopoietic stem cell generation. Our findings provide a valuable cross-species resource, advancing our understanding of human pre-circulation yolk sac hematopoiesis and offering a theoretical basis for the regeneration of functional blood cells.