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

doi:10.1038/s41586-022-04571-x

Mapping human haematopoietic stem cells from haemogenic endothelium to birth

Nature. 2022 Apr;604(7906):534-540. doi: 10.1038/s41586-022-04571-x. Epub 2022 Apr 13.

Authors

Vincenzo Calvanese^#^{1

2

3}, Sandra Capellera-Garcia^#^{4

5}, Feiyang Ma^#^{4

5

6}, Iman Fares^{4

5}, Simone Liebscher⁷, Elizabeth S Ng⁸, Sophia Ekstrand^{4

5}, Júlia Aguadé-Gorgorió^{4

5}, Anastasia Vavilina^{4

5}, Diane Lefaudeux^{9

10}, Brian Nadel⁴, Jacky Y Li⁸, Yanling Wang⁴, Lydia K Lee¹¹, Reza Ardehali^{5

12}, M Luisa Iruela-Arispe¹³, Matteo Pellegrini^{4

5}, Ed G Stanley^{8

14

15}, Andrew G Elefanty^{8

14

15}, Katja Schenke-Layland^{7

12

16

17}, Hanna K A Mikkola^{18

19}

Affiliations

¹ Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA. v.calvanese@ucl.ac.uk.
² Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA. v.calvanese@ucl.ac.uk.
³ Laboratory for Molecular Cell Biology, University College London, London, UK. v.calvanese@ucl.ac.uk.
⁴ Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA.
⁵ Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA.
⁶ Chongqing International Institute for Immunology, Chongqing, China.
⁷ Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University, Tübingen, Germany.
⁸ Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia.
⁹ Signaling Systems Laboratory, Department of Microbiology Immunology and Molecular Genetics (MIMG), University of California Los Angeles, Los Angeles, CA, USA.
¹⁰ Institute for Quantitative and Computational Biosciences (QCB), University of California Los Angeles, Los Angeles, CA, USA.
¹¹ Department of Obstetrics and Gynecology, University of California Los Angeles, Los Angeles, CA, USA.
¹² Department of Medicine/Cardiology, CVRL, University of California Los Angeles, Los Angeles, CA, USA.
¹³ Cell and Developmental Biology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
¹⁴ Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia.
¹⁵ Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.
¹⁶ Cluster of Excellence iFIT (EXC 2180) 'Image-Guided and Functionally Instructed Tumor Therapies', Eberhard Karls University Tübingen, Tübingen, Germany.
¹⁷ NMI Natural and Medical Sciences Institute, University Tübingen, Reutlingen, Germany.
¹⁸ Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA. hmikkola@mcdb.ucla.edu.
¹⁹ Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA. hmikkola@mcdb.ucla.edu.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Differentiation
Endothelial Cells*
Endothelium
Female
Hematopoiesis
Hematopoietic Stem Cells*
Humans
Mesonephros
Pregnancy

Abstract

Publication types

MeSH terms

Grants and funding