Extravillous trophoblast differentiation is modulated by KLF6 transcription factor through reactive oxygen species.

KOURDOVA, LUCILLE T.; MIRANDA, ANDREA L.; RACCA, ANA C.; ROJAS MARÍA LAURA; CRUZ DEL PUERTO, MARIANO; RAMALHO, M JULIANA; BORBELY, ALEXANDRE U.; CASTRO, CLAUDIA; GENTI DE RAIMONDI SUSANA; PANZETA DE DUTARI GRACIELA

Congreso; Reuniones de Sociedades de Biociencias 2021; 2021

During placental development, extravillous trophoblasts (EVT) acquirean invasive and migratory phenotype to anchor the placenta tothe uterus. Alterations in these processes are associated with pathologiessuch as preeclampsia and placenta accreta spectrum. KLF6is a transcription factor highly expressed in placenta and requiredfor proper placental development. KLF6 immunoreactivity is higherin the placental bed of preeclamptic than in that of uncomplicatedpregnancies. Its expression is regulated by hypoxia and inducersof oxidative stress. Reactive Oxygen Species (ROS) modulate essentialphysiological processes but can lead to oxidative or reductivedamage. We have demonstrated that KLF6 silencing increasesROS level and EVT cell migration. We hypothesize that KLF6 modulatesEVT differentiation through ROS. Herein, we demonstrate thatROS induced upon KLF6 downregulation is not associated with celldamage, based on Anexin V/7-AAD and MTT assays. Cell proliferation,measured by BrdU uptake, is reduced and correlates withan increase in p21 expression. In addition, the decrease in KLF6levels increase metalloproteinase 9 activity and the expression ofmolecules involved in cell migration, promotes the translocation ofβ-catenin to the nucleus, measured by confocal microscopy, andincreases polarized cell migration evaluated by orientation of themicrotubule organizing center. Furthermore, KLF6-silenced cellsacquire a more fibroblastic phenotype and treatment with two antioxidants,NAC and tempol, partially recovers cell morphology. In linewith the data obtained in vitro, placenta accretas, characterized bybeing abnormally invasive, have lower KLF6 immunostaining levels.Altogether these results suggest that KLF6 modulates EVT differentiationthrough the regulation of ROS levels and suggest that itsdysregulation may contribute to the development of pregnancy pathologieslike placenta accreta spectrum and preeclampsia.