Glutamine metabolism regulates endothelial to hematopoietic transition and hematopoietic lineage specification

During hematopoietic development, definitive hematopoietic cells are derived from hemogenic endothelial (HE) cells through a process known as endothelial to hematopoietic transition (EHT). During EHT, transitioning cells proliferate and undergo progressive changes in gene expression culminating in the new cell identity with corresponding changes in function, phenotype and morphology. However, the metabolic pathways fueling this transition remain unclear. We show here that glutamine is a crucial regulator of EHT and a rate limiting metabolite in the hematopoietic differentiation of HE cells. Intriguingly, different hematopoietic lineages require distinct derivatives of glutamine. While both derivatives, α-ketoglutarate and nucleotides, are required for early erythroid differentiation of HE during glutamine deprivation, lymphoid differentiation relies on α-ketoglutarate alone. Furthermore, treatment of HE cells with α-ketoglutarate in glutamine-free conditions pushes their differentiation towards lymphoid lineages both in vitro and in vivo, following transplantation into NSG mice. Thus, we report an essential role for glutamine metabolism during EHT, regulating both the emergence and the specification of hematopoietic cells through its various derivatives.