Expression and Function of the Iron Transport Protein, Ferroportin, at the Maternal-Fetal Interface.

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Ng, Shu-Wing
Lee, Chungyan
Ng, Allen C
Ng, Shu-Kay
Arcuri, Felice
Toti, Paolo
Norwitz, Errol R
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Introduction: Iron is required to support feto-placental development. However, iron overload has been associated with abnormal decidualization, pregnancy complications including pre-eclampsia (PE) and spontaneous preterm birth (sPTB), and endometriosis. Ferroportin (Fpn) is the only known mammalian iron exporter, and plays an essential role in the export of iron from storage to blood for distribution to tissues. We hypothesize that Fpn is a critical regulator of iron homeostasis and ferroptosis (irondependent programmed cell death) at the maternal-fetal interface. To this end, we investigated the expression of Fpn in placentas/fetal membranes from normal/abnormal pregnancies and endometriosis tissues. Fpn function was tested in immortalized human endometrial stromal cells (HESCs) and first trimester extravillous trophoblast cells (Sw.71) with knockdown of Fpn expression. Methods: Immunohistochemistry for Fpn expression was performed in placentas/fetal membranes from 7 term births, 8 PE, and 3 sPTB, as well as 8 endometriosis tissues. HESC and Sw.71 cell lines with stable knockdown of Fpn expression were established using lentiviral short-hairpin RNAs. Iron overload was induced by increasing doses of ferric ammonium citrate (FAC) and the effect on cell growth measured by MTT assay. Results: Fpn was highly expressed in amnion, chorion, and decidual cells in fetal membranes; in placental trophoblasts; and in epithelial and stromal cells in endometriosis tissues. Fpn expression was significantly different in fetal membranes from term birth, PE, and sPTB (P=0.014, Kruskal-Wallis test), with a reduction in sPTB versus term birth (P=0.046, Mann-Whitney analysis with Bonferroni correction). Fpn staining in fetal membranes was also significantly correlated with gestational length (r=0.617, P=0.006). In contrast, Fpn staining in the placenta was not significantly different between the three groups (P=0.052), and did not correlate with gestational length (P=0.147). Fpn knockdown in Sw. cells did not affect cell proliferation under basal conditions. However, in the setting of iron overload, Fpn knockdown in Sw.71 cells increased sensitivity of the cells to high doses of FAC. Conclusion: The iron export protein Fpn is highly expressed in eutopic and ectopic endometrium, placental tissues, and fetal membranes. Fpn expression was significantly reduced in fetal membranes from sPTB. Functional studies suggest a critical role for Fpn in maintaining iron homeostasis and ferroptosis at the maternal-fetal interface.

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Ng, S-W; Lee, C; Ng, AC; Ng, S-K; Arcuri, F; Toti, P; Norwitz, ER, Expression and Function of the Iron Transport Protein, Ferroportin, at the Maternal-Fetal Interface., Reproductive Sciences, 2019, 26, pp. 199A-199A