Abstract
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.
Highlights
During hematopoietic development, definitive hematopoietic cells are derived from hemogenic endothelial (HE) cells through a process known as endothelial to hematopoietic transition (EHT)
All hematopoietic cells derived in the three hematopoietic waves arise from endothelial c ells[6,7,8] and definitive hematopoietic development starts with a specialized set of endothelial cells with hemogenic potential that differentiate towards hematopoietic cells through a process known as endothelial to hematopoietic transition (EHT)[9,10]
To determine whether glutamine is important for fueling the tricarboxylic acid (TCA) cycle during EHT, we blocked the glutaminase (GLS) enzyme, which catalyzes the deamidation of glutamine to glutamate, by treating HE cells with an allosteric glutaminase inhibitor, bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) (Fig. 1a)
Summary
Definitive hematopoietic cells are derived from hemogenic endothelial (HE) cells through a process known as endothelial to hematopoietic transition (EHT). All hematopoietic cells derived in the three hematopoietic waves arise from endothelial c ells[6,7,8] and definitive hematopoietic development starts with a specialized set of endothelial cells with hemogenic potential that differentiate towards hematopoietic cells through a process known as endothelial to hematopoietic transition (EHT)[9,10]. The in vitro differentiation from induced pluripotent stem cells (iPSCs) appears to recapitulate aspects of primitive and definitive hematopoietic waves, with the generation of both primitive erythroid cells expressing embryonic and fetal globins, as well as lymphoid cells among other hematopoietic c ells[11,12,13,14], making it an ideal system to study specific regulators involved in human hematopoietic cell development. We describe an important role for glutamine during EHT, both for the proliferation of transitioning cells and their differentiation into distinct hematopoietic lineages
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