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

Placenta progenitor cells, also known as trophoblasts, initially specify at very low oxygen (O2) concentrations. Across their differentiation path in the uterine microenvironment, they encounter a wide range of O2 levels. Despite previous efforts, dissecting how these rapid and dynamic O2 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 O2 levels of the uterine microenvironment, and by genetically ablating HIF1 in human trophoblast organoids, we found that O2 availability and HIF pathway independently control trophoblast lineage specification, maturation and function. Specifically, low O2 levels promote expansion of extravillous trophoblast (EVT) progenitors independently of HIF1, while HIF1 is necessary for EVT invasion regardless of O2 availability. Altogether, our results reveal a dual regulatory framework that disentangles the role of O2 from that of HIF1, offering a revised view of how O2 availability regulates early human placental development.