HER1 Signaling Mediates Extravillous Trophoblast Differentiation in Humans

HER1 Signaling Mediates Extravillous Trophoblast Differentiation in HumansExtravillous trophoblast (EVT) migration and invasion into the maternal decidua are critical aspects of normal human placentation. The process of EVT invasion leads to the transformation of the maternal spiral arteries into large-diameter, low-resistance, high-flow vessels capable of supplying adequate blood into the intervillous space to nourish the growing conceptus. In normal pregnancies the depth of trophoblast invasion is strictly regulated to ensure adequate access of placental cells to the maternal spiral arteries. The importance of this regulation is underscored by the pathologies of pregnancy that arise from aberrant invasion; for instance, preeclampsia is marked by hypoinvasion of the trophoblast into the decidua and a failure of vascular remodeling, whereas choriocarcinoma, invasive moles, and placenta accreta are characterized by hyperinvasion of the trophoblast into maternal tissues.
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The EVT population of the placenta is phenotypically heterogeneous, comprised of both proliferative and invasive cells. When the proliferative EVT of the placental cell column contact the maternal decidua, they become invasive cells capable of moving through and colonizing the decidual stroma. This differentiation event is tightly regulated both temporally and spatially such that the EVT of the cell columns are proliferative but noninvasive, and the invasive EVT cells within the decidual stroma have no proliferative capacity. The transition between the proliferative and invasive EVT phenotypes is associated with changes in the expression profiles of several proteins: connexin-40 (Cx40), MKI67, EGF receptor (HER1), and the a5 integrin are expressed by proliferative EVT; the EGF recepto5r c-erb-B2 (HER2) and the a1 integrin are expressed by invasive EVT.
Previous investigations by our group into the mechanisms regulating the differentiation of EVT demonstrated that treatment of villous explants with decidua-conditioned media (DCM) initiated a complete differentiation of EVT from the proliferative to the invasive phenotype. Under these conditions, EVT not only downregulated MKI67, Cx40, and a5 integrin and upregulated a1integrin expression, but also downregulated HER1 expression and began to express HER2. In JAR cells, DCM treatment downregulated Cx40 expression and induced cell migration. Notably, AG1478, a potent and specific inhibitor of HER1 tyrosine kinase activity, blocked the DCM-induced differentiation effects on JAR cells. These findings suggested that activation of HER1 and its downstream signaling pathways may be important for initiating the differentiation of invasive EVT. However, when we treated JAR cells with EGF (one of many HER1 ligands) in a transwell migration assay, it did not induce any JAR cell migration, suggesting that specific HER1 activation, via another HER1 ligand, was required to prompt JAR cell migration

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