Abstract
Complete hydatidiform mole (HM) is a gestational trophoblastic disease resulting in hyperproliferation of trophoblast cells and absence of embryo development. Mutations in the maternal-effect gene NLRP7 are the major cause of familial recurrent complete HM. Here, we established an in vitro model of HM using patient-specific induced pluripotent stem cells (iPSCs) derived trophoblasts harboring NLRP7 mutations. Using whole transcriptome profiling during trophoblast differentiation, we showed that impaired NLRP7 expression results in precocious downregulation of pluripotency factors, activation of trophoblast lineage markers, and promotes maturation of differentiated extraembryonic cell types such as syncytiotrophoblasts. Interestingly, we found that these phenotypes are dependent on BMP4 signaling and BMP pathway inhibition corrected the excessive trophoblast differentiation of patient-derived iPSCs. Our human iPSC model of a genetic placental disease recapitulates aspects of trophoblast biology, highlights the broad utility of iPSC-derived trophoblasts for modeling human placental diseases and identifies NLRP7 as an essential modulator of key developmental cell fate regulators.
Highlights
Maternal-effect genes encode for proteins, deposited into oocytes, which are required for embryonic development[1]
No difference was observed between hydatidiform mole (HM) and WT cells in terms of reprogramming efficiency and maintenance of pluripotency under standard culture conditions (Fig. 1b–d). induced pluripotent stem cells (iPSCs) expressed pluripotency markers OCT4, NANOG, SOX2, LIN28A, and LIN28B as assessed by immunofluorescence and RT-PCR (Fig. 1c, d). iPSC lines were karyotypically normal, devoid of episomal reprogramming vectors, and could readily differentiate into cell types belonging to three germ layers in a teratoma formation assay in immunocompromised mice (Fig. S1a–c)
None of the groups were completely positive for HLA-G and presence of CDX2 positive areas on day 4 pointed to a heterogeneous differentiation stage
Summary
Maternal-effect genes encode for proteins, deposited into oocytes, which are required for embryonic development[1]. Mutations in such genes result in embryonic phenotypes that reflect the genotype of the mother rather than that of the offspring[2]. Null phenotypes of a majority of these genes result in arrested development at very early embryonic time points[3]. NLR proteins, Nlrp[5] (Mater) and Nlrp[2], both of which are required for early embryonic development of mice and have unknown functions[11,12]. In contrast to mice models of maternal-effect genes, embryos of affected women with
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