人造血干细胞从血液内皮细胞到出生

Human hematopoietic stem cell (HSC) ontogeny is poorly defined due to the inability to identify HSCs as they emerge and mature in different hematopoietic sites. We created a single-cell transcriptome map of human hematopoietic tissues from 1st trimester to birth and found that HSC signature RUNX1+HOXA9+MLLT3+MECOM+HLF+SPINK2+ distinguishes HSCs from progenitors throughout gestation. In addition to the AGM (aorta-gonad-mesonephros) region, nascent HSCs populated the placenta and yolk sac before colonizing the liver at 6 weeks. Comparison of HSCs from different maturation stages revealed the establishment of HSC transcription factor machinery upon HSC emergence, whereas their surface phenotype evolved throughout development. HSC transition to the liver marked a molecular shift evidenced by suppression of surface antigens, reflecting nascent HSC identity, and acquisition of HSC maturity markers PROM1/CD133 and HLA-DR. HSC origin was tracked to ALDH1A1+KCNK17+ hemogenic endothelial (HE) cells, which arose from IL33+ALDH1A1+ arterial endothelial subset, termed pre-HE. Spatial transcriptomics and immunofluorescence visualized this process in ventrally located intra-aortic hematopoietic clusters. The in vivo map of human HSC ontogeny validated the generation of AGM-like definitive HSPCs from human pluripotent stem cells, and serves as a guide to improve their maturation to functional HSCs.