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Efficient generation of human NOTCH ligand-expressing haemogenic endothelial cells as infrastructure for in vitro haematopoiesis and lymphopoiesis

Author

Listed:
  • Shicheng Sun

    (The Royal Children’s Hospital
    Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne
    Murdoch Children’s Research Institute
    Changping Laboratory)

  • Ali Motazedian

    (The Royal Children’s Hospital
    Peter MacCallum Cancer Centre
    The University of Melbourne)

  • Jacky Y. Li

    (The Royal Children’s Hospital
    Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne
    Murdoch Children’s Research Institute)

  • Kevin Wijanarko

    (The Royal Children’s Hospital
    Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne
    Murdoch Children’s Research Institute)

  • Joe Jiang Zhu

    (Peter MacCallum Cancer Centre
    The University of Melbourne)

  • Kothila Tharmarajah

    (The Royal Children’s Hospital
    Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne
    Murdoch Children’s Research Institute)

  • Kathleen A. Strumila

    (The Royal Children’s Hospital
    Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne
    Murdoch Children’s Research Institute)

  • Anton Shkaruta

    (The Royal Children’s Hospital
    Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne
    Murdoch Children’s Research Institute)

  • L. Rayburn Nigos

    (The Royal Children’s Hospital
    Murdoch Children’s Research Institute)

  • Jacqueline V. Schiesser

    (The Royal Children’s Hospital
    Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne
    Murdoch Children’s Research Institute)

  • Yi Yu

    (The Royal Children’s Hospital
    Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne)

  • Paul J. Neeson

    (Peter MacCallum Cancer Centre
    The University of Melbourne)

  • Elizabeth S. Ng

    (The Royal Children’s Hospital
    Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne
    Murdoch Children’s Research Institute)

  • Andrew G. Elefanty

    (The Royal Children’s Hospital
    Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne
    Murdoch Children’s Research Institute)

  • Edouard G. Stanley

    (The Royal Children’s Hospital
    Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne
    Murdoch Children’s Research Institute)

Abstract

Arterial endothelial cells (AECs) are the founder cells for intraembryonic haematopoiesis. Here, we report a method for the efficient generation of human haemogenic DLL4+ AECs from pluripotent stem cells (PSC). Time-series single-cell RNA-sequencing reveals the dynamic evolution of haematopoiesis and lymphopoiesis, generating cell types with counterparts present in early human embryos, including stages marked by the pre-haematopoietic stem cell genes MECOM/EVI1, MLLT3 and SPINK2. DLL4+ AECs robustly support lymphoid differentiation, without the requirement for exogenous NOTCH ligands. Using this system, we find IL7 acts as a morphogenic factor determining the fate choice between the T and innate lymphoid lineages and also plays a role in regulating the relative expression level of RAG1. Moreover, we document a developmental pathway by which human RAG1+ lymphoid precursors give rise to the natural killer cell lineage. Our study describes an efficient method for producing lymphoid progenitors, providing insights into their endothelial and haematopoietic ontogeny, and establishing a platform to investigate the development of the human blood system.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51974-7
    DOI: 10.1038/s41467-024-51974-7
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