Mapping human haematopoietic stem cells from haemogenic endothelium to birth

Vincenzo Calvanese*, Sandra Capellera-Garcia, Feiyang Ma, Iman Fares, Simone Liebscher, Elizabeth S. Ng, Sophia Ekstrand, Júlia Aguadé-Gorgorió, Anastasia Vavilina, Diane Lefaudeux, Brian Nadel, Jacky Y. Li, Yanling Wang, Lydia K. Lee, Reza Ardehali, M. Luisa Iruela-Arispe, Matteo Pellegrini, Ed G. Stanley, Andrew G. Elefanty, Katja Schenke-LaylandHanna K.A. Mikkola

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

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 sites1. 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.

Original languageEnglish (US)
Pages (from-to)534-540
Number of pages7
JournalNature
Volume604
Issue number7906
DOIs
StatePublished - Apr 21 2022

ASJC Scopus subject areas

  • General

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