An immune cell atlas reveals the dynamics of human macrophage specification during prenatal development

Macrophages are heterogeneous and play critical roles in development and disease, but their diversity, function, and specification remain inadequately understood during human development. We generated a single-cell RNA sequencing map of the dynamics of human macrophage specification from PCW 4–26 across 19 tissues. We identified a microglia-like population and a proangiogenic population in 15 macrophage subtypes. Microglia-like cells, molecularly and morphologically similar to microglia in the CNS, are present in the fetal epidermis, testicle, and heart. They are the major immune population in the early epidermis, exhibit a polarized distribution along the dorsal-lateral-ventral axis, and interact with neural crest cells, modulating their differentiation along the melanocyte lineage. Through spatial and differentiation trajectory analysis, we also showed that proangiogenic macrophages are perivascular across fetal organs and likely yolk-sac-derived as microglia. Our study provides a comprehensive map of the heterogeneity and developmental dynamics of human macrophages and unravels their diverse functions during development. [Display omitted] •A spatial and temporal molecular roadmap of human prenatal macrophages•Extensive and distinctive distribution of microglia-like cells outside the CNS•Microglia-like cells in the skin interact with and regulate neural crest cells•A proangiogenic macrophage population that is perivascular across fetal organs A single-cell RNA sequencing map of human immune cells from postconceptional weeks 4–26 across 19 tissues is provided with a focus on macrophage specification. Of note, a microglia-like cell population widely distributed outside the CNS as well as a proangiogenic population were found among the 15 macrophage subtypes identified.