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-Layland and Hanna K. A. Mikkola ()
Additional contact information
Vincenzo Calvanese: University of California Los Angeles
Sandra Capellera-Garcia: University of California Los Angeles
Feiyang Ma: University of California Los Angeles
Iman Fares: University of California Los Angeles
Simone Liebscher: Eberhard Karls University
Elizabeth S. Ng: The Royal Children’s Hospital
Sophia Ekstrand: University of California Los Angeles
Júlia Aguadé-Gorgorió: University of California Los Angeles
Anastasia Vavilina: University of California Los Angeles
Diane Lefaudeux: University of California Los Angeles
Brian Nadel: University of California Los Angeles
Jacky Y. Li: The Royal Children’s Hospital
Yanling Wang: University of California Los Angeles
Lydia K. Lee: University of California Los Angeles
Reza Ardehali: University of California Los Angeles
M. Luisa Iruela-Arispe: Northwestern University, Feinberg School of Medicine
Matteo Pellegrini: University of California Los Angeles
Ed G. Stanley: The Royal Children’s Hospital
Andrew G. Elefanty: The Royal Children’s Hospital
Katja Schenke-Layland: Eberhard Karls University
Hanna K. A. Mikkola: University of California Los Angeles

Nature, 2022, vol. 604, issue 7906, 534-540

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-04571-x

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