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Research Article

Preeclamptic placentae release factors that damage neurons: implications for foetal programming of disease

Hannah Scott, Tom J. Phillips, Greer C. Stuart, Mark F. Rogers, Bruno R. Steinkraus, Simon Grant, C. Patrick Case
Neuronal Signaling Oct 12, 2018, 2 (4) NS20180139; DOI: 10.1042/NS20180139
Hannah Scott
School of Clinical Sciences, University of Bristol, Learning & Research Building, Southmead Hospital, Bristol BS10 5NB, U.K.UK Dementia Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, U.K.
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  • http://orcid.org/0000-0002-2497-549X
  • For correspondence: ScottH6@cardiff.ac.uk
Tom J. Phillips
School of Clinical Sciences, University of Bristol, Learning & Research Building, Southmead Hospital, Bristol BS10 5NB, U.K.UK Dementia Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, U.K.
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Greer C. Stuart
Department of Obstetrics, Southmead Hospital, Bristol BS10 5NB, U.K.
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Mark F. Rogers
Intelligent Systems Laboratory, University of Bristol, Merchant Venturers Building, Woodland Road, Bristol BS8 1UB, U.K.
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Bruno R. Steinkraus
Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, U.K.
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Simon Grant
Department of Obstetrics, Southmead Hospital, Bristol BS10 5NB, U.K.
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C. Patrick Case
School of Clinical Sciences, University of Bristol, Learning & Research Building, Southmead Hospital, Bristol BS10 5NB, U.K.
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  • Figure 1
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    Figure 1 Effects of healthy and PE medium on mixed cortical cultures

    Mixed cortical cultures were exposed to medium conditioned by healthy (n=6) or preeclamptic (n=6) placental explants that had been pre-treated with no NPs, blank-NPs or MitoQ-NPs. Following a 24-h exposure, cortical cultures were assessed for neuronal dendrite lengths (A), process lengths of TH+ cells (B), levels of glutamate receptor subunits GluN1 (C) and GluN3α (D), levels of GABA receptor subunits GABA Aα1 (E) and GABA B1 (F), along with astrocyte count (G) and astrocyte process lengths (H). Data are presented as means + S.E.M.; *P<0.05, **P<0.01, ***P<0.001.

  • Figure 2
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    Figure 2 Role of glutamate inhibition in mediating effects of PE medium on mixed cortical cultures

    Mixed cortical cultures were incubated with NMDA receptor antagonist MK801 prior to exposure to culture medium conditioned by healthy (n=6) or preeclamptic (n=6) placental explants that had been treated with no NPs or with MitoQ-NPs. Lengths of neuronal dendrites (A), lengths of TH+ cell processes (B) and levels of glutamate receptor subunit GluN1 (C) were measured in the cortical cultures (data are presented as means + S.E.M.; ***P<0.001).

  • Figure 3
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    Figure 3 Role of astrocytes in mediating effects of PE medium on neurons

    (A–C) Neuron-only cortical cultures were exposed directly to medium conditioned by healthy or preeclamptic placental explants, which had been pre-treated with no NPs, blank-NPs or MitoQ-NPs. (D–F) In a second experiment, neuron-only cultures were exposed to medium collected from astrocyte-only cortical cultures, which had previously been exposed to the placenta conditioned medium, and some neuronal cultures were additionally pre-treated with NMDA receptor antagonist MK801. Neuronal dendrite lengths (A,D), TH+ process lengths (B,E) and glutamate receptor subunit GluN1 levels (C,F) were measured (data are presented as means + S.E.M.; *P<0.05, **P<0.01, ***P<0.001).

  • Figure 4
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    Figure 4 Role of neurons in mediating effects of PE medium on astrocytes

    (A and B) Astrocyte-only cortical cultures were exposed directly to medium conditioned by healthy or preeclamptic placental explants, which had been pre-treated with no NPs, blank-NPs or MitoQ-NPs. (C–F) In a second experiment, astrocyte-only cultures were exposed to medium collected from neuron-only cortical cultures, which had previously been exposed to the placenta conditioned medium. Astrocyte cultures were assessed with regard to cell count (A and E), process lengths (B and F) along with levels of glutamate receptor subunits GluN1 (C) and GluN3α (D) (data are presented as means + S.E.M.; **P<0.01, ***P<0.001).

  • Figure 5
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    Figure 5 Characterization of PE conditioned medium

    (A) Total levels of proteinogenic amino acids (µmol/l ± S.E.M.) were measured in culture medium conditioned by healthy (n=3) or preeclamptic (n=3) placental explants, following pre-treatment with no NPs, blank-NPs or MitoQ-NPs. (B) Log 2 fold change values are shown for those microRNAs that were significantly altered in PE medium (n=4) compared with healthy medium (n=4) (blue). Log fold changes of those same microRNAs in medium conditioned by preeclamptic placental explants treated with MitoQ-NPs (n=3), compared with untreated PE medium, are shown in orange.

  • Figure 6
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    Figure 6 Overview of potential mechanistic effects of PE medium on cortical cultures

    Secreted molecules from the preeclamptic placenta, including potentially microRNAs, may have direct effects on neurons and astrocytes. Some of the effects of PE medium on cortical cultures may also be indirect via glutamate secretion from astrocytes or by secretion of unknown factors from neurons.

  • Figure 7
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    Figure 7 Overview of experimental setup

    Culture medium conditioned by healthy or preeclamptic placental explants, following exposure to no NPs, blank-NPs or MitoQ-NPs, was applied to mixed cortical cultures, astrocyte-only cortical cultures or neuron-only cortical cultures (A). To establish the role of astrocytes in mediating the effects of placenta-conditioned medium on cortical cultures, culture medium from the exposed astrocyte-only cultures was applied to neuron-only cultures (B); in order to investigate the role of neurons in mediating the effects of placenta condition medium on cortical cultures, culture medium from neuron-only cultures that had been exposed to placenta-conditioned medium was applied to astrocyte-only cultures (C).

Tables

  • Figures
  • Table 1 Amino acid concentration in μmol/l (±S.E.M.) in medium conditioned by healthy (n=3) or preeclamptic placentas (n=3), after exposure to no NPs, blank-NPs or MitoQ-NPs
    HealthyPE
    Amino acidNo NPBlank-NPMitoQ-NPNo NPBlank-NPMitoQ-NP
    Ala79.27 (45.02)90.93 (64.43)54.77 (24.70)79.70 (52.22)64.07 (42.47)251.0 (228.84)
    Arg357.0 (5.483)335.7 (33.79)331.8 (19.46)336.6 (6.552)332.7 (17.84)371.1 (26.71)
    Asn16.63 (16.63)21.33 (21.33)7.833 (7.833)15.07 (15.07)11.70 (11.70)94.13 (94.13)
    Asp0 (0)0 (0)0 (0)0 (0)0 (0)67.17 (67.17)
    Cys58.63 (7.636)58.10 (2.001)62.60 (7.614)67.57 (4.927)69.83 (4.190)66.27 (4.983)
    Gln1509 (396.8)1411 (275.0)1358 (318.2)1293 (436.2)1273 (442.3)1464 (477.7)
    Glu64.73 (53.55)67.90 (67.90)36.10 (30.62)41.00 (24.97)62.97 (50.80)201.4 (188.5)
    Gly409.4 (34.20)384.3 (51.72)356.8 (24.70)398.9 (30.74)393.3 (52.11)585.4 (223.0)
    His153.3 (12.70)143.4 (21.24)142.9 (15.69)127.8 (7.503)139.2 (10.12)185.2 (59.89)
    Ile702.4 (35.45)629.6 (17.69)647.5 (28.17)683.4 (48.12)682.9 (46.88)770.0 (59.13)
    Leu554.4 (192.9)674.5 (23.68)671.0 (24.70)725.4 (30.02)720.2 (53.58)908.5 (177.8)
    Lys736.7 (17.91)674.5 (36.12)675.6 (26.43)726.3 (15.76)721.9 (61.11)890.9 (170.8)
    Met171.6 (7.270)154.1 (4.206)152.5 (7.878)162.5 (10.52)175.0 (13.83)208.4 (40.77)
    Phe377.8 (14.26)344.5 (15.59)346.3 (14.85)386.8 (9.103)390.2 (33.93)467.3 (79.52)
    Pro86.00 (17.56)87.20 (34.33)72.50 (12.85)146.1 (66.25)100.4 (33.79)252.7 (188.6)
    Ser377.4 (9.481)346.9 (23.40)342.9 (13.37)369.1 (13.16)358.1 (31.58)514.3 (151.0)
    Thr740.6 (23.73)671.67 (27.48)679.6 (27.09)711.6 27.48)716.3 (53.71)829.0 (106.1)
    Trp0 (0)0 (0)0 (0)0 (0)0 (0)23.73 (23.73)
    Tyr366.2 (10.53)330.2 (14.00)336.4 (13.60)364.8 (12.40)355.7 (26.76)433.0 (60.29)
    Val733.8 (27.62)673.4 (23.32)671.8 (26.17)734.27 (27.35)741.7 (56.19)893.6 (153.5)
  • Table 2 Enriched biological processes
    Biological processCountFold enrichmentP value
    Sensory perception of chemical stimulus3<0.23.20E-23
    Developmental process4681.531.99E-17
    Sensory perception of smell1<0.21.17E-16
    Intracellular signal transduction2621.674.44E-13
    Sensory perception400.383.47E-11
    Signal transduction5181.374.18E-11
    MAPK cascade1082.161.16E-10
    Cell communication5651.341.88E-10
    Cell cycle2261.595.55E-09
    Nervous system development1731.641.42E-07
    System development2481.475.14E-07
    Cellular process14611.138.56E-07
    Death1181.743.21E-06
    Cell death1181.743.21E-06
    • Results of gene ontology analysis of predicted targets of differentially abundant microRNAs in PE placenta conditioned medium compared with healthy placental conditioned medium are listed. P values have been corrected for multiple comparisons using FDR.

  • Table 3 Top 15 enriched pathways
    KEGG pathwayCountFold enrichmentP value
    MAPK signalling pathway1062.401.11E-17
    Ras signalling pathway892.275.58E-13
    Pathways in cancer1271.861.51E-11
    Neurotrophin signalling pathway552.648.13E-11
    Rap1 signalling pathway792.171.58E-10
    PI3K-Akt signalling pathway1121.871.89E-10
    Melanoma373.004.36E-09
    Axon guidance532.418.11E-09
    ErbB signalling pathway412.721.44E-08
    FoxO signalling pathway542.321.98E-08
    Renal cell carcinoma332.937.95E-08
    T-cell receptor signalling pathway442.469.83E-08
    Signalling pathways regulating pluripotency of stem cells542.229.61E-08
    Regulation of actin cytoskeleton711.942.24E-07
    Insulin signalling pathway522.174.19E-07
    • Results of KEGG pathway analysis of predicted targets of differentially abundant microRNAs in PE placenta conditioned medium compared with healthy placental conditioned medium are listed. P values have been corrected for multiple comparisons using Benjamini–Hochberg method.

  • Table 4 microRNAs significantly affected in preeclampsia and by MitoQ-NP treatment
    microRNAKnown relevant functions
    Up-regulated in PE
    hsa-miR-561-5pRegulates 11β-HSD1, which is highly expressed in liver, adipose tissue and CNS [96]
    Associated with Parkinson’s disease [97]
    hsa-miR-548ai+hsa-miR-570-5pmiR-570 associated with autism [98] and congenital heart disease [99]
    miR-570 regulates cytochrome P450 [100]
    hsa-miR-196b-5pAssociated with ectopic pregnancy [101]
    Associated with endometriosis [102]
    hsa-miR-2117None
    hsa-miR-3065-3pNone
    Down-regulated in PE
    hsa-miR-596None
    hsa-miR-451aAssociated with type 2 diabetes [103]
    • Listed are those microRNAs that were found to be up- or down-regulated in culture medium conditioned by preeclamptic placental explants, compared with healthy explants, and that were also affected in the opposite direction by treatment of the placenta with MitoQ-NPs but not blank-NPs.

  • Table 5 Clinical data of collected preeclamptic placentae
    GestationParitySeverityPCRIUGRCo-morbidities
    1*35+50Moderate274Unknownn/a
    2*37+30Moderate361Non/a
    3*†‡40+82Mild204Non/a
    4*40+130Moderate331NoHypothyroid
    5*‡370Severe427UnknownDM1
    6*‡27+40Severe537YesAPKD
    7*†‡26+11Severe448YesSLE nephritis, previous DVT/pulmonary embolus, baby has metabolic disorder
    8*†38+44Severe32Non/a
    • APKD, adult polycystic kidney disease; DM1, type 1 diabetes; DVT, deep vein thrombosis; IUGR, intrauterine growth restriction; PCR, protein-creatinine ratio; SLE, systemic lupus erythematosus. Conditioned media from the highlighted placentas was *applied to cortical cultures; †analysed for amino acids; ‡analysed for microRNA.

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December 2018

Volume: 2 Issue: 4

Neuronal Signaling: 2 (4)
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Preeclamptic placentae release factors that damage neurons: implications for foetal programming of disease
Hannah Scott, Tom J. Phillips, Greer C. Stuart, Mark F. Rogers, Bruno R. Steinkraus, Simon Grant, C. Patrick Case
Neuronal Signaling Dec 2018, 2 (4) NS20180139; DOI: 10.1042/NS20180139
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Preeclamptic placentae release factors that damage neurons: implications for foetal programming of disease
Hannah Scott, Tom J. Phillips, Greer C. Stuart, Mark F. Rogers, Bruno R. Steinkraus, Simon Grant, C. Patrick Case
Neuronal Signaling Dec 2018, 2 (4) NS20180139; DOI: 10.1042/NS20180139

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Keywords

astrocytes
glutamate
microRNA
neurodevelopmental disorders
neurons
preeclampsia

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