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

formato virtual

Congreso; SAIC. SAI. AAFE. NANOMED-AR; 2021

During placental development, extravillous trophoblasts (EVT) acquire an invasive and migratory phenotype to anchor the placenta to the uterus. Alterations in these processes are associated with pathologies such as preeclampsia and placenta accreta spectrum. KLF6 is a transcription factor highly expressed in placenta and required for proper placental development. KLF6 immunoreactivity is higher in the placental bed of preeclamptic than in that of uncomplicated pregnancies. Its expression is regulated by hypoxia and inducers of oxidative stress. Reactive Oxygen Species (ROS) modulate essential physiological processes but can lead to oxidative or reductive damage. We have demonstrated that KLF6 silencing increases ROS level and EVT cell migration. We hypothesize that KLF6 modulates EVT differentiation through ROS. Herein, we demonstrate that ROS induced upon KLF6 downregulation is not associated with cell damage, based on Anexin V/7-AAD and MTT assays. Cell proliferation, measured by BrdU uptake, is reduced and correlates with an increase in p21 expression. In addition, the decrease in KLF6 levels increase metalloproteinase 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 organizing center. Furthermore, KLF6-silenced cells acquire a more fibroblastic phenotype and treatment with two antioxidants, NAC and tempol, partially recovers cell morphology. In line with the data obtained in vitro, placenta accretas, characterized by being abnormally invasive, have lower KLF6 immunostaining levels. Altogether these results suggest that KLF6 modulates EVT differentiation through the regulation of ROS levels and suggest that its dysregulation may contribute to the development of pregnancy pathologies like placenta accreta spectrum and preeclampsia.