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Abstract
The members of the NR4A family of nuclear hormone receptors, NR4A1-3, play important albeit redundant roles in maintaining adult hematopoietic stem cell quiescence and vascular homeostasis. However, the roles of these receptors in the development of hematopoietic and endothelial cell lineages remain largely unexplored, due to embryonic lethality observed in knockout mice and limited human data. In this study, we utilize human embryonic stem cell (hESC)-based in vitro models to investigate the roles of the NR4A family in hematopoietic progenitor cell (HPC) formation via endothelial-to-hematopoietic transition in single, double, and triple NR4A knockout hESC cultures. We observed the formation of CD31+ cells expressing lymphatic endothelial cell markers in NR4A-deleted cultures, suggesting a novel progenitor role for NR4A receptors in lymphatic-like endothelial cell differentiation. Additionally, NR4A deletion increases HPC population accompanied by sustained expression of HPC markers, indicating enhanced HPC generation and/or maintenance in knockout cultures.