RT Journal Article SR Electronic T1 Low oxygen enhances trophoblast column growth by potentiating the extravillous lineage and promoting LOX activity JF bioRxiv FD Cold Spring Harbor Laboratory SP 669796 DO 10.1101/669796 A1 Jenna Treissman A1 Victor Yuan A1 Jennet Baltayeva A1 Hoa T. Le A1 Barbara Castellana A1 Wendy P. Robinson A1 Alexander G. Beristain YR 2019 UL http://biorxiv.org/content/early/2019/06/12/669796.abstract AB Early placental development and the establishment of the invasive trophoblast lineage take place within a low oxygen environment. However, conflicting and inconsistent findings have obscured the role of oxygen in regulating invasive trophoblast differentiation. In this study, the effect of hypoxic, normoxic, and atmospheric oxygen on invasive extravillous pathway progression was examined using a human placental explant model. Here, we show that exposure to low oxygen enhances extravillous column outgrowth and promotes the expression of genes that align with extravillous trophoblast (EVT) lineage commitment. By contrast, super-physiological atmospheric levels of oxygen promote trophoblast proliferation while simultaneously stalling EVT progression. Low oxygen-induced EVT differentiation coincided with elevated transcriptomic levels of lysyl oxidase (LOX) in trophoblast anchoring columns, where functional experiments established a role for LOX activity in promoting EVT column outgrowth. The findings of this work support a role for low oxygen in potentiating the differentiation of trophoblasts along the extravillous pathway. Additionally, these findings generate insight into new molecular processes controlled by oxygen during early placental development.Summary Statement Low oxygen promotes extravillous trophoblast differentiationBAPNβ-aminopropionitrileBrdUBromodeoxyuridineCMConditioned mediaCTBCytotrophoblastDAP1,5-diaminopentaneDCTDistal column trophoblastDGEDifferential gene expressionECMExtracellular matrixEVTExtravillous trophoblastFDRFalse discovery rateGOGene ontologyHIF1AHypoxia inducible factor 1 AHLA-GHuman leukocyte antigen GHrHourIFImmunofluorescenceLOXLysyl oxidasePCAPrincipal component analysisPCTProximal column trophoblastPEG10Paternally expressed gene 10scRNA-seqsingle cell RNA sequencingSCTSyncytiotrophoblastUMAPUniform manifold approximation and projectionvCTBVillous cytotrophoblast