Mapping human haematopoietic stem cells from haemogenic endothelium to birth

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...

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Published inNature (London) Vol. 604; no. 7906; pp. 534 - 540
Main Authors Calvanese, Vincenzo, Capellera-Garcia, Sandra, Ma, Feiyang, Fares, Iman, Liebscher, Simone, Ng, Elizabeth S., Ekstrand, Sophia, Aguadé-Gorgorió, Júlia, Vavilina, Anastasia, Lefaudeux, Diane, Nadel, Brian, Li, Jacky Y., Wang, Yanling, Lee, Lydia K., Ardehali, Reza, Iruela-Arispe, M. Luisa, Pellegrini, Matteo, Stanley, Ed G., Elefanty, Andrew G., Schenke-Layland, Katja, Mikkola, Hanna K. A.
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 21.04.2022
Nature Publishing Group
Subjects
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14
38
38/91
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631/532/1542
Antigens
Aorta
Birth
Cell Differentiation
Coronary vessels
Endothelial Cells
Endothelium
Female
Gene expression
Hematopoiesis
Hematopoietic Stem Cells
Histocompatibility antigen HLA
Humanities and Social Sciences
Humans
Immunofluorescence
Liver
Maturation
Mesonephros
multidisciplinary
Ontogeny
Phenotypes
Placenta
Pluripotency
Potassium channels
Pregnancy
Progenitor cells
Runx1 protein
Science
Science (multidisciplinary)
Stem cells
Surface antigens
Transcriptomes
Transcriptomics
Yolk sac
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Summary: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. The HSC signature RUNX1 + HOXA9 + MLLT3 + MECOM + HLF + SPINK2 + distinguishes haematopoietic stem cells from their endothelial precursors and differentiated progenitors throughout ontogeny
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These authors contributed equally.
V.C., S.C.G. and H.K.A.M. designed experiments and interpreted data. F.M. led the bioinformatic analysis, which was also performed by V.C. and S.C.G. and assisted by I.F., S.E., B.N. and J.L. V.C. and S.C.G. performed and/or supervised wet lab experiments and related data analysis, assisted by I.F. and J.A.G. S.L. coordinated the tissue collection and procurement and performed the immunofluorescence experiments. A.V. assisted with immunofluorescence data analysis. E.S.N., E.G.S., J.L. and A.G.E. generated the hPSC in vitro differentiation data. D.L. established the web interface for data mining, R.A., L.I.A., L.L, M.P. and K.S-L. assisted with data interpretation and contextualization. V.C., S.C.G. and H.K.A.M. wrote the manuscript, which all authors edited and approved.
Author contributions
ISSN:0028-0836
1476-4687
1476-4687
DOI:10.1038/s41586-022-04571-x