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Mapping human haematopoietic stem cells from haemogenic endothelium to birth

Author

Listed:
  • Vincenzo Calvanese

    (University of California Los Angeles
    University of California Los Angeles
    University College London)

  • Sandra Capellera-Garcia

    (University of California Los Angeles
    University of California Los Angeles)

  • Feiyang Ma

    (University of California Los Angeles
    University of California Los Angeles
    Chongqing International Institute for Immunology)

  • Iman Fares

    (University of California Los Angeles
    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
    University of California Los Angeles)

  • Júlia Aguadé-Gorgorió

    (University of California Los Angeles
    University of California Los Angeles)

  • Anastasia Vavilina

    (University of California Los Angeles
    University of California Los Angeles)

  • Diane Lefaudeux

    (University of California Los Angeles
    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
    University of California Los Angeles)

  • M. Luisa Iruela-Arispe

    (Northwestern University, Feinberg School of Medicine)

  • Matteo Pellegrini

    (University of California Los Angeles
    University of California Los Angeles)

  • Ed G. Stanley

    (The Royal Children’s Hospital
    University of Melbourne
    Monash University)

  • Andrew G. Elefanty

    (The Royal Children’s Hospital
    University of Melbourne
    Monash University)

  • Katja Schenke-Layland

    (Eberhard Karls University
    University of California Los Angeles
    Eberhard Karls University Tübingen
    University Tübingen)

  • Hanna K. A. Mikkola

    (University of California Los Angeles
    University of California Los Angeles)

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.

Suggested Citation

  • Vincenzo Calvanese & Sandra Capellera-Garcia & Feiyang Ma & Iman Fares & Simone Liebscher & Elizabeth S. Ng & Sophia Ekstrand & Júlia Aguadé-Gorgorió & Anastasia Vavilina & Diane Lefaudeux & Brian Nad, 2022. "Mapping human haematopoietic stem cells from haemogenic endothelium to birth," Nature, Nature, vol. 604(7906), pages 534-540, April.
    • Handle: RePEc:nat:nature:v:604:y:2022:i:7906:d:10.1038_s41586-022-04571-x
    DOI: 10.1038/s41586-022-04571-x
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    Cited by:

    1. Shicheng Sun & Ali Motazedian & Jacky Y. Li & Kevin Wijanarko & Joe Jiang Zhu & Kothila Tharmarajah & Kathleen A. Strumila & Anton Shkaruta & L. Rayburn Nigos & Jacqueline V. Schiesser & Yi Yu & Paul , 2024. "Efficient generation of human NOTCH ligand-expressing haemogenic endothelial cells as infrastructure for in vitro haematopoiesis and lymphopoiesis," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Xiaoyi Cheng & Radwa Barakat & Giulia Pavani & Masuma Khatun Usha & Rodolfo Calderon & Elizabeth Snella & Abigail Gorden & Yudi Zhang & Paul Gadue & Deborah L. French & Karin S. Dorman & Antonella Fid, 2023. "Nod1-dependent NF-kB activation initiates hematopoietic stem cell specification in response to small Rho GTPases," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    3. Shuyang Cai & Honghu Li & Ruxiu Tie & Wei Shan & Qian Luo & Shufen Wang & Cong Feng & Huiqiao Chen & Meng Zhang & Yulin Xu & Xia Li & Ming Chen & Jiahui Lu & Pengxu Qian & He Huang, 2024. "Nlrc3 signaling is indispensable for hematopoietic stem cell emergence via Notch signaling in vertebrates," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    4. Rita Silvério-Alves & Ilia Kurochkin & Anna Rydström & Camila Vazquez Echegaray & Jakob Haider & Matthew Nicholls & Christina Rode & Louise Thelaus & Aida Yifter Lindgren & Alexandra Gabriela Ferreira, 2023. "GATA2 mitotic bookmarking is required for definitive haematopoiesis," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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