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

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 J. Neeson, Elizabeth S. Ng, Andrew G. Elefanty and Edouard G. Stanley ()
Additional contact information
Shicheng Sun: The Royal Children’s Hospital
Ali Motazedian: The Royal Children’s Hospital
Jacky Y. Li: The Royal Children’s Hospital
Kevin Wijanarko: The Royal Children’s Hospital
Joe Jiang Zhu: Peter MacCallum Cancer Centre
Kothila Tharmarajah: The Royal Children’s Hospital
Kathleen A. Strumila: The Royal Children’s Hospital
Anton Shkaruta: The Royal Children’s Hospital
L. Rayburn Nigos: The Royal Children’s Hospital
Jacqueline V. Schiesser: The Royal Children’s Hospital
Yi Yu: The Royal Children’s Hospital
Paul J. Neeson: Peter MacCallum Cancer Centre
Elizabeth S. Ng: The Royal Children’s Hospital
Andrew G. Elefanty: The Royal Children’s Hospital
Edouard G. Stanley: The Royal Children’s Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51974-7

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