Oxygen availability and hypoxia-independent action of HIF1α controls human trophoblast maturation and function

SUMMARY Placenta progenitor cells, also known as trophoblasts, initially specify at very low oxygen (O 2 ) concentrations. Across their differentiation path in the uterine microenvironment, they encounter a wide range of O 2 levels. Despite previous efforts, dissecting how these rapid and dynamic O 2 levels are sensed by trophoblast stem cells and transduced via hypoxia inducible factors (HIFs) has been challenging and has led to conflicting conclusions. This is at least in part due to the lack of tractable and reliable methods to model human placental development. Here, by recapitulating the dynamic O 2 levels of the uterine microenvironment, and by genetically ablating HIF1α in human trophoblast organoids, we found that O 2 availability and HIF pathway independently control trophoblast lineage specification, maturation and function. Specifically, low O 2 levels promote expansion of extravillous trophoblast (EVT) progenitors independently of HIF1α, while HIF1α is necessary for EVT invasion regardless of O 2 availability. Altogether, our results reveal a dual regulatory framework that disentangles the role of O 2 from that of HIF1α, offering a revised view of how O 2 availability regulates early human placental development.