Efficient generation of human NOTCH ligand-expressing haemogenic endothelial cells as infrastructure for in vitro haematopoiesis and lymphopoiesis
Details
Publication Year 2024-09-04,Volume 15,Issue #1,Page 7698
Journal Title
Nature Communications
Publication Type
Research article
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.
Publisher
Springer Nature
Keywords
Humans; *Hematopoiesis/genetics; *Lymphopoiesis/genetics; Endothelial Cells/metabolism/cytology; Cell Differentiation; Cell Lineage/genetics; Interleukin-7/metabolism/genetics; Pluripotent Stem Cells/metabolism/cytology; Calcium-Binding Proteins/metabolism/genetics; Adaptor Proteins, Signal Transducing/metabolism/genetics; Killer Cells, Natural/metabolism/cytology; Hemangioblasts/metabolism/cytology; Hematopoietic Stem Cells/cytology/metabolism; Homeodomain Proteins/metabolism/genetics; Single-Cell Analysis/methods; Receptors, Notch/metabolism/genetics
Department(s)
Laboratory Research
Terms of Use/Rights Notice
Refer to copyright notice on published article.


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