EXTRAVILLOUS TROPHOBLAST DIFFERENTIATION IS MODULATED BY KLF6 TRANSCRIPTION FACTOR THROUGH REACTIVE OXYGEN SPECIES

KOURDOVA, LUCILLE T; MIRANDA, ANDREA L; RACCA, ANA C.; ROJAS, MARIA L.; CRUZ DEL PUERTO, MARIANO; MARQUES, A.; BORBELY, A.; CASTRO, C.; GENTI-RAIMONDI, S.; PANZETTA-DUTARI, GRACIELA M.

Mar del Plata

Congreso; Reunión Conjunta 2021; 2021

SAIC SAI SAFE

During placental development, extravillous trophoblasts (EVT) acquire an invasive andmigratory phenotype to anchor the placenta to the uterus. Alterations in these processes areassociated with pathologies such as preeclampsia and placenta accreta spectrum. KLF6 is atranscription factor highly expressed in placenta and required for proper placentaldevelopment. KLF6 immunoreactivity is higher in the placental bed of preeclamptic than inthat of uncomplicated pregnancies. Its expression is regulated by hypoxia and inducers ofoxidative stress. Reactive Oxygen Species (ROS) modulate essential physiologicalprocesses but can lead to oxidative or reductive damage. We have demonstrated that KLF6silencing increases ROS level and EVT cell migration. We hypothesize that KLF6 modulatesEVT differentiation through ROS. Herein, we demonstrate that ROS induced upon KLF6downregulation is not associated with cell damage, based on Anexin V/7-AAD and MTTassays. Cell proliferation, measured by BrdU uptake, is reduced and correlates with anincrease in p21 expression. In addition, the decrease in KLF6 levels increasemetalloproteinase 9 activity and the expression of molecules involved in cell migration,promotes the translocation of β-catenin to the nucleus, measured by confocal microscopy,and increases polarized cell migration evaluated by orientation of the microtubule organizingcenter. Furthermore, KLF6-silenced cells acquire a more fibroblastic phenotype andtreatment with two antioxidants, NAC and tempol, partially recovers cell morphology. In linewith the data obtained in vitro, placenta accretas, characterized by being abnormallyinvasive, have lower KLF6 immunostaining levels. Altogether these results suggest thatKLF6 modulates EVT differentiation through the regulation of ROS levels and suggest thatits dysregulation may contribute to the development of pregnancy pregnancy pathologies like placenta accreta spectrum and preeclampsia.