Krüppel‐like factor 6 participates in extravillous trophoblast cell differentiation and its expression is reduced in abnormally invasive placenta

Trophoblast cell differentiation is of paramount importance for successful pregnancy. Krüppel‐like factor 6 (KLF6), a transcription factor with diverse roles in cell physiology and tumor biology, is required for trophoblast differentiation through the syncytial pathway. Herein, we demonstrate that extravillous trophoblast (EVT) cell migration and mesenchymal phenotype are increased upon KLF6 downregulation or the expression of a deletion mutant lacking its transcriptional regulatory domain (KΔac). Raman spectroscopy revealed molecular modifications compatible with increased differentiation in cells stably expressing the KΔac mutant. Moreover, abnormally invasive placenta showed lower KLF6 immunostaining compared with the normal placenta. Thus, impaired KLF6 expression or function stimulates EVT migration and differentiation in vitro and may contribute to the physiopathology of the abnormally invasive placenta. Cytotrophoblast differentiation into migratory extravillous trophoblasts (EVT) is critical for human placentation. This study shows that the downregulation of the transcription factor KLF6 or the loss of its transcriptional activity modulates EVT differentiation by regulating cell migration and EVT mesenchymal phenotype. Placentas from the placenta accreta spectrum show less KLF6 expression than those from uncomplicated pregnancies. Thus, KLF6 dysregulation may be involved in placental physiopathology.