Mapping human haematopoietic stem cells from haemogenic endothelium to birth.
Vincenzo CalvaneseSandra Capellera-GarciaFeiyang MaIman FaresSimone LiebscherElizabeth S NgSophia EkstrandJúlia Aguadé-GorgorióAnastasia VavilinaDiane LefaudeuxBrian B NadelJacky Y LiYanling WangLydia K LeeReza ArdehaliM Luisa Iruela-ArispeMatteo PellegriniEd G StanleyAndrew G ElefantyKatja Schenke-LaylandHanna K A MikkolaPublished in: Nature (2022)
The ontogeny of human haematopoietic stem cells (HSCs) is poorly defined owing to the inability to identify HSCs as they emerge and mature at different haematopoietic sites 1 . Here we created a single-cell transcriptome map of human haematopoietic tissues from the first trimester to birth and found that the HSC signature RUNX1 + HOXA9 + MLLT3 + MECOM + HLF + SPINK2 + distinguishes HSCs from progenitors throughout gestation. In addition to the aorta-gonad-mesonephros region, nascent HSCs populated the placenta and yolk sac before colonizing the liver at 6 weeks. A comparison of HSCs at different maturation stages revealed the establishment of HSC transcription factor machinery after the emergence of HSCs, whereas their surface phenotype evolved throughout development. The HSC transition to the liver marked a molecular shift evidenced by suppression of surface antigens reflecting nascent HSC identity, and acquisition of the HSC maturity markers CD133 (encoded by PROM1) and HLA-DR. HSC origin was tracked to ALDH1A1 + KCNK17 + haemogenic endothelial cells, which arose from an IL33 + ALDH1A1 + arterial endothelial subset termed pre-haemogenic endothelial cells. Using spatial transcriptomics and immunofluorescence, we visualized this process in ventrally located intra-aortic haematopoietic clusters. The in vivo map of human HSC ontogeny validated the generation of aorta-gonad-mesonephros-like definitive haematopoietic stem and progenitor cells from human pluripotent stem cells, and serves as a guide to improve their maturation to functional HSCs.
Keyphrases
- endothelial cells
- pluripotent stem cells
- single cell
- stem cells
- transcription factor
- high glucose
- aortic valve
- gene expression
- preterm infants
- nitric oxide
- radiation therapy
- rna seq
- vascular endothelial growth factor
- high throughput
- dna methylation
- heart failure
- pulmonary hypertension
- long non coding rna
- mass spectrometry
- high density
- cell therapy