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Nature
04, 2022;604 (7906): 534-540.

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, Hanna K A Mikkola
Author Information
  1. Vincenzo Calvanese: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA. v.calvanese@ucl.ac.uk. ORCID
  2. Sandra Capellera-Garcia: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA.
  3. Feiyang Ma: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA. ORCID
  4. Iman Fares: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA.
  5. Simone Liebscher: Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University, Tübingen, Germany.
  6. Elizabeth S Ng: Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia.
  7. Sophia Ekstrand: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA.
  8. Júlia Aguadé-Gorgorió: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA. ORCID
  9. Anastasia Vavilina: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA.
  10. Diane Lefaudeux: Signaling Systems Laboratory, Department of Microbiology Immunology and Molecular Genetics (MIMG), University of California Los Angeles, Los Angeles, CA, USA.
  11. Brian Nadel: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA. ORCID
  12. Jacky Y Li: Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia.
  13. Yanling Wang: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA.
  14. Lydia K Lee: Department of Obstetrics and Gynecology, University of California Los Angeles, Los Angeles, CA, USA.
  15. Reza Ardehali: Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA. ORCID
  16. M Luisa Iruela-Arispe: Cell and Developmental Biology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA. ORCID
  17. Matteo Pellegrini: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA.
  18. Ed G Stanley: Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia.
  19. Andrew G Elefanty: Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia. ORCID
  20. Katja Schenke-Layland: Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University, Tübingen, Germany. ORCID
  21. Hanna K A Mikkola: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA. hmikkola@mcdb.ucla.edu. ORCID
PMID: 35418685 DOI: 10.1038/s41586-022-04571-x

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 sites. Here we created a single-cell transcriptome map of human haematopoietic tissues from the first trimester to birth and found that the HSC signature RUNX1HOXA9MLLT3MECOMHLFSPINK2 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 ALDH1A1KCNK17 haemogenic endothelial cells, which arose from an IL33ALDH1A1 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.

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Grants

  1. R01 HL148714/NHLBI NIH HHS
  2. R35 HL140014/NHLBI NIH HHS
  3. T32 HL086345/NHLBI NIH HHS
  4. R01 DK100959/NIDDK NIH HHS
  5. T32 HL069766/NHLBI NIH HHS
  6. R01 DK125097/NIDDK NIH HHS
  7. R01 DK121557/NIDDK NIH HHS
  8. P30 CA016042/NCI NIH HHS
  9. P30 AI028697/NIAID NIH HHS

MeSH Term

Cell Differentiation
Endothelial Cells
Endothelium
Female
Hematopoiesis
Hematopoietic Stem Cells
Humans
Mesonephros
Pregnancy
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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