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Current model systems for the study of preeclampsia
Article in Experimental Biology and Medicine · February 2018

DOI: 10.1177/1535370218755690
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Experimental Biology and Medicine
Current model systems for the study of preeclampsia
Journal: Experimental Biology and Medicine

Manuscript ID EBM-17-MR-0239.R2
Manuscript Type: Mini-Reviews
Date Submitted by the Author: 29-Dec-2017
F
Complete List of Authors: Martinez-Fierro, Margarita L; Molecular Medicine Laboratory. Unidad
Académica de Medicina Humana y Ciencias de la Salud, Universidad
Autónoma de Zacatecas.; Bioengineering Laboratory. Centro de
r Investigación e Innovación Tecnológica Industrial (CIITI), Universidad

Autónoma de Zacatecas.
Hernández-Delgadillo, Gloria P; Laboratorio de Investigación en
Peer
Farmacología, Universidad Autónoma de Zacatecas.
Flores-Morales, Virginia; Laboratorio de Síntesis Asimétrica y Bioenergética
(LSAyB), Universidad Autónoma de Zacatecas.
Cardenas-Vargas, Edith; Molecular Medicine Laboratory. Unidad Académica
de Medicina Humana y Ciencias de la Salud, Universidad Autónoma de
Zacatecas.; Hospital General Zacatecas "Luz Gonzalez Cosio", Secretaria
de Salud de Zacatecas.
Mercado-Reyes, Marisa; Laboratorio de Biología de la Conservación, Unidad
Revie
Académica de Ciencias Biológicas, Universidad Autónoma de Zacatecas.
Rodriguez-Sanchez, Iram P; Departamento de Genetica, Facultad de
Medicina, Universidad Autonoma de Nuevo Leon
Delgado-Enciso, Ivan; Faculty of Medicine, Universidad de Colima; State
w
Cancer Institute, Health Secretary of Colima
Galván-Tejada, Carlos E; Unidad Académica de Ingeniería Eléctrica,
Universidad Autónoma de Zacatecas.
Galván-Tejada, Jorge I; Unidad Académica de Ingeniería Eléctrica,
Universidad Autónoma de Zacatecas.
Celaya-Padilla, Jose M; Unidad Académica de Ingeniería Eléctrica,
Universidad Autónoma de Zacatecas.; CONACYT – Universidad Autónoma
de Zacatecas.
Garza-Veloz, Idalia; Molecular Medicine Laboratory. Unidad Académica de
Medicina Humana y Ciencias de la Salud, Universidad Autónoma de
Zacatecas.; Bioengineering Laboratory. Centro de Investigación e
Innovación Tecnológica Industrial (CIITI), Universidad Autónoma de
Zacatecas.
MODELS, SYSTEMS, PRESSURE, PREGNANCY, BIOLOGY/PHYSIOLOHY,
Keywords:
BIOMEDICAL
Preeclampsia (PE) is a pregnancy complex disease, distinguished by high
blood pressure and proteinuria, diagnosed after the 20th gestation week.
Depending on the values of blood pressure, urine protein concentrations,
symptomatology and onset of disease there is a wide range of phenotypes,
Abstract: from mild forms developing predominantly at the end of pregnancy to
severe forms developing in the early stage of pregnancy. In the worst
cases severe forms of PE could lead to systemic endothelial dysfunction,
eclampsia and maternal and/or fetal death. Worldwide the fetal morbidity
and mortality related to PE is calculated to be around 8 % of the total
https://mc.manuscriptcentral.com/ebm
Page 1 of 63 Experimental Biology and Medicine
1
2
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pregnancies. PE still being an enigma regarding its etiology and
4
pathophysiology, in general a deficient trophoblast invasion during
5 placentation at first stage of pregnancy, in combination with maternal
6 conditions is accepted as a cause of endothelial dysfunction, inflammatory
7 disorders and appearance of symptoms. Depending on the PE multifactorial
8 origin, several in vitro, in vivo and in silico models have been used to
9 evaluate the PE pathophysiology as well as to identify or test biomarkers
predicting, diagnosing or prognosing the syndrome. This review focusses
10
on the most common models used for the study of PE, including those
11 related to placental development, abnormal trophoblast invasion,
12 uteroplacental ischemia, angiogenesis, oxygen deregulation and immune
13 response to maternal-fetal interactions. The advances in mathematical and
14 computational modelling of metabolic network behavior, gene prioritization,
15 the protein-protein interaction network, the genetics of PE and the PE
prediction/classification are discussed. Finally, the potential of these
16
models to enable understanding of PE pathogenesis and to evaluate new
17
For
preventative and therapeutic approaches in the management of PE are also
18 highlighted.
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Experimental Biology and Medicine Page 2 of 63
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3 1 Current model systems for the study of preeclampsia
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5 2 Martinez-Fierro ML1, 2, Hernández-Delgadillo GP3, Flores-Morales V4, Cardenas-
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3 Vargas E1, 5, Mercado-Reyes M6, Rodriguez-Sanchez IP7, Delgado-Enciso I8, 9, Galván-
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9 10 10 10, 11 1, 2, †
10 4 Tejada CE , Galván-Tejada JI , Celaya-Padilla JM , Garza-Veloz I .
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13 5 1. Molecular Medicine Laboratory. Unidad Académica de Medicina Humana y Ciencias
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15 6 de la Salud, Universidad Autónoma de Zacatecas. Carretera Zacatecas-Guadalajara
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17 7 Km.6. Ejido la Escondida, C.P. 98160 Zacatecas, Mexico.
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19 8 2. Bioengineering Laboratory. Centro de Investigación e Innovación Tecnológica
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21 9 Industrial (CIITI), Universidad Autónoma de Zacatecas. Av. Ramón López Velarde No.
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23 10 801, Col. Centro, C.P. 98000 Zacatecas, Mexico.
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11 3. Laboratorio de Investigación en Farmacología, Universidad Autónoma de Zacatecas.
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28 12 Carretera Zacatecas-Guadalajara Km.6. Ejido la Escondida, C.P. 98160 Zacatecas,
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30 13 Mexico.
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32 14 4. Laboratorio de Síntesis Asimétrica y Bioenergética (LSAyB), Universidad Autónoma
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34 15 de Zacatecas. Carretera Zacatecas-Guadalajara Km.6. Ejido la Escondida, C.P. 98160
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36 16 Zacatecas, Mexico.
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17 5. Hospital General Zacatecas "Luz Gonzalez Cosio", Secretaria de Salud de Zacatecas.
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41 18 Circuito Ciudad Gobierno No. 410. Col. Ciudad Gobierno. Zacatecas, México.
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43 19 6. Laboratorio de Biología de la Conservación, Unidad Académica de Ciencias
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45 20 Biológicas, Universidad Autónoma de Zacatecas. Calzada Solidaridad esq. Paseo, La
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47 21 Bufa, C.P. 98060, Zacatecas, Mexico.
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49 22 7. Departamento de Genetica, Facultad de Medicina, Universidad Autonoma de Nuevo
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23 Leon, Monterrey, Nuevo Leon, Mexico.
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54 24 8. Faculty of Medicine, Universidad de Colima, Colima, Mexico.
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3 25 9. State Cancer Institute, Health Secretary of Colima, Colima, Mexico.
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5 26 10. Unidad Académica de Ingeniería Eléctrica, Universidad Autónoma de Zacatecas,
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7 27 Jardín Juárez 147, Centro, 98000 Zacatecas, Mexico.
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9 28 11. CONACYT – Universidad Autónoma de Zacatecas, Jardín Juárez 147, Centro,
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11 98000 Zacatecas, Mexico.
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14 30
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†
16 31 Corresponding Author:
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18 32 Idalia Garza-Veloz, D.Sc.
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20 33 Unidad Académica de Medicina Humana y Ciencias de la Salud. Universidad
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22 34 Autónoma de Zacatecas. Email: idaliagv@uaz.edu.mx
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3 36 Abstract
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5 37 Preeclampsia (PE) is a pregnancy complex disease, distinguished by high blood
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7 38 pressure and proteinuria, diagnosed after the 20th gestation week. Depending on the
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9 39 values of blood pressure, urine protein concentrations, symptomatology and onset of
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11 disease there is a wide range of phenotypes, from mild forms developing predominantly
40
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41 at the end of pregnancy to severe forms developing in the early stage of pregnancy. In
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16 42 the worst cases severe forms of PE could lead to systemic endothelial dysfunction,
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18 43 eclampsia and maternal and/or fetal death. Worldwide the fetal morbidity and mortality
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20 44 related to PE is calculated to be around 8 % of the total pregnancies. PE still being an
21
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22 45 enigma regarding its etiology and pathophysiology, in general a deficient trophoblast
23
24 invasion during placentation at first stage of pregnancy, in combination with maternal
46
25
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47 conditions is accepted as a cause of endothelial dysfunction, inflammatory disorders and
27
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29 48 appearance of symptoms. Depending on the PE multifactorial origin, several in vitro, in
30
31 49 vivo and in silico models have been used to evaluate the PE pathophysiology as well as
32
33 50 to identify or test biomarkers predicting, diagnosing or prognosing the syndrome. This
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35 51 review focusses on the most common models used for the study of PE, including those
36
37 52 related to placental development, abnormal trophoblast invasion, uteroplacental
38
39
ischemia, angiogenesis, oxygen deregulation and immune response to maternal-fetal
40 53
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54 interactions. The advances in mathematical and computational modelling of metabolic
42
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44 55 network behavior, gene prioritization, the protein-protein interaction network, the
45
46 56 genetics of PE and the PE prediction/classification are discussed. Finally, the potential
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48 57 of these models to enable understanding of PE pathogenesis and to evaluate new
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50 58 preventative and therapeutic approaches in the management of PE are also highlighted.
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60 Keywords: Model systems, study, preeclampsia.
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3 61 Impact Statement:
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5 62 This review is important to the field of preeclampsia (PE), because it provides a present
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7 63 description of the principal in vitro, in vivo and in silico models developed for the study
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9 64 of its principal aspects, and to test emerging therapies or biomarkers predicting the
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11 syndrome before their evaluation in clinical trials. Despite of the current advance, the
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66 field still lacking of new methods and original modelling approaches that leads to new
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16 67 knowledge about pathophysiology. The part of in silico models described in this review
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18 68 has not been considered in the previous reports.
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20 69
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22 70 Introduction
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24 Preeclampsia (PE), a pregnancy-specific disorder distinguished by high blood pressure
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72 and proteinuria as a consequence of abnormal placentation, is diagnosed after the 20th
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29 73 week of gestation (WG). A heighten systemic vascular resistance, endothelial cell
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31 74 dysfunction, platelet aggregation, and activation of the coagulation system have been
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33 75 associated with PE, representing one of the principal responsible of perinatal and
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35 76 maternal morbimortality worldwide, especially in developing countries, affecting 5–8 %
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37 77 of all pregnancies (1, 2). Clinical manifestations of PE include a maternal syndrome
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(proteinuria (≥300 mg in 24-hour urine) and high blood pressure (≥140/90 mm Hg))
40 78
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79 with or without other multisystem abnormalities such as edema, headache, renal failure,
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44 80 epigastric pain, low platelet count and abnormal liver enzyme values) and fetal
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46 81 syndrome (hypoxemia, diminished amniotic fluid and small-for gestational age) (2).
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48 82 Exist several theories about the ultimate cause of PE, and nowadays it is thought that
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50 83 the etiology is most likely multifactorial. The appearance of the disease can be
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influenced by several predisposingoftenness
factors.
and severityThe
of PE are
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considerably elevated in women with multifetal pregnancies, chronic high blood
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1
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3 86 pressure, a personal and family history of PE, pre-existing diabetes mellitus and
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5 87 thrombophilia (3). The presence of high concentrations of circulating
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7 88 syncytiotrophoblast debris, genetic susceptibility, maternal immunological alterations,
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9 89 nutritional factors and an increased sensitivity to angiotensin (AT) II could play a
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11 fundamental part in the etiology of PE (2, 4-6).
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91 As referred before, it is widely recognized that a deficient placentation process is the
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16 92 primary cause of PE. In a normal pregnancy, endovascular trophoblast invasion
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For
transform the spiral arteries of the decidual part at 8 – 10 WG (first invasion) and of the
myometrial part at 16 – 18 WG (second invasion), invading the arterial wall and
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22 95 expanding its diameter from narrow to large by replacing normal musculoelastic to
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24 amorphous fibrinoid tissue of the arteries, allowing with this physiological
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97 transformation an adequate blood flow of the placenta (7, 8). Failure of the second
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29 98 trophoblast invasion with an abnormal physiological transformation of the spiral arteries
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31 99 are observed in PE, directing to placental ischemia-reperfusion, oxidative stress,
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33 100 endothelial dysfunction (a disequilibrium among pro and anti-angiogenic proteins with
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35 101 a predominance of the last one) and the origin of the clinical manifestations of disease
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102 (9).
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103 Because PE-related cellular and/or molecular abnormalities occur between 16 and 18
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104 WG, the impossibility of obtaining placental tissues from early stages of gestation and
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44 105 the delayed clinical manifestations of PE (until after 26 to 28 WG in its earliest form, or
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46 106 after 34 to 36 WG in late PE (10)) represent the two biggest problems in the study of
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48 107 this disease. Accordingly, the approaches to study PE mostly depend on specimens
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50 108 (placentas) obtained after delivery, limiting the findings and information to relatively
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late PE manifestations. Intrinsic complications in the in vitro and in vivo research of
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3 110 placental implication to this human disease necessitate the development of model
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5 111 systems.
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7 112 Since no model by itself has thoroughly reproduced this affection, a diversity of in vitro,
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9 113 in vivo and in silico techniques have been employed, as well as several ‘PE-like’ models
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114 (4). This review focusses on the most common models used for the study of PE,
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115 including those related to placental development, abnormal trophoblast invasion,
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16 116 uteroplacental ischemia, angiogenesis, oxygen deregulation and immune response to
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For
maternal-fetal interactions. The mathematical and computational perspective commonly
employed to model gene prioritization, protein-protein interaction network analysis,

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119 metabolic network behavior, the genetics of PE, and the PE prediction and classification
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120 are discussed. Finally, the potential of these models to understand the pathophysiology
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121 of PE, as well as to evaluate prevention actions and new treatment strategies in the
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29 122 control of this pregnancy-specific disorder, is also highlighted.
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31 123
32 124 In vitro models of PE
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34 125 Four types of in vitro models for PE have been described in the literature: 1) cell
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36 126 cultures, 2) placental explants, 3) co-cultures and 4) placental organ cultures (See Figure
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127 1 and Table 1 in Supplementary material file 1).
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128 In PE these models are used to elucidate the mechanism controlling trophoblast cell
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43 129 lineage development, as well as for analysis of trophoblast invasion, endocrine function,
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45 130 immune response, oxygen dysregulation, metabolism, transport, syncytium formation,
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47 131 morphogenesis and adaptation to disease, and placental development, and to assess the
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49 132 effect of PE biomarkers or molecules with therapeutic potentials (11-14).
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133 The experimental approaches include isolating, culturing, establishing and manipulating
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134 primary cell line cultures from trophoblast, malignant choriocarcinoma, embryonal lines
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3 135 with trophoblast differentiation and stem cells from mammalians (humans, rodents such
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5 136 as mice, golden hamsters, rats and rabbits, bovines, pigs, sheep, and non-human
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7 137 primates such as rhesus monkeys and marmosets) (15).
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9 138 In particular, trophoblast cell lines can be obtained through the culture of primary
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139 villous, extravillous and placental cells, or from already established trophoblastic cell
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140 lines (obtained from normal or malignant cells). Several of these cell lines have been
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16 141 virus transfected, such as cell lines from HTR-8/SVneo and SGHPL cells, acquiring the
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For
advantage of longer proliferation in culture than primary cells (16). To extend the
utilization of these cell lines, the International Federation of Placenta Associations

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144 (IFPA) covenanted the biological criteria for the characterization of established
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145 trophoblast cell lines and primary cell cytotrophoblast cultures, in a trophoblast cell line
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146 workshop at the European Placenta Group (EPG) meeting in 1999 (17). The current
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29 147 villous trophoblast cell model most widely used is the choriocarcinoma cell line BeWo
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31 148 due to it displays most of the attributes of villous trophoblast, such as the formation of
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33 149 syncytiotrophoblast fusion by regulation of syncytin-1 gene expression as well as
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35 150 secretion of human chorionic gonadotropin, prolactin, progesterone and estradiol (16).
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151 Some of the drawbacks of the primary cell cultures are that they cease to proliferate and
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dedifferentiate when they lose cell-cell interaction, contact with secreted signaling
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153 molecules and/or 3D extracellular matrix structure (18). To overcome these limitations,
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44 154 3D co-culture models and placental explants have been developed, allowing these
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46 155 important cellular interactions to function as an ordered multicellular arrangement
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48 156 where the cells can take advantage of resources and execute functions that would be not
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50 157 possible as individual cells (18). There are two different types of placental explant
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culture: A) Early placental cultures for the study of invasion and differentiation of the
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159 extravillous trophoblast. This could be first-trimester placental villi explanted on gels of
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3 160 a permissive extracellular matrix or a standard trans-filter trophoblast migration started
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5 161 from a homogeneous preparation of primary cells released from the tissue (19). B) Term
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7 162 placental cultures for the evaluation of villous trophoblast proliferation and function,
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9 163 and for assessing preventive and therapeutic agents for PE (20).
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164 With regard to 3D co-culture models, co-cultures of trophoblasts with peripheral blood
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165 mononuclear cells, macrophage, neutrophils or NK cells have been developed to
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16 166 evaluate the immune response and trophoblast-immune cell interactions (13, 21-24). In
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18 167 the same vein, in the evaluation of cell proliferation, migration, invasion and endothelial
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20 168 cell interactions, co-cultures of human umbilical vein endothelial cells (HUVECs) and
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22 169 trophoblasts grown in low oxygenation conditions have been performed (25-27). Co-
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170 culture of trophoblast and human uterine myometrial microvascular endothelial cells, or
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171 with human endometrial endothelial cells, has also been used to evaluate the oxygen
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29 172 dysregulation effects (28). In all the mentioned models of placental cells, different co-
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31 173 culture matrix compounds in a 3D conformation have been tested, including collagen
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33 174 and matrigel, among others (21, 26).
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35 175 Investigate the human placenta constitutes a major experimental feat. In spite of the cell
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176 culture, co-cultures and explants have been used as essential tools for the study of
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177 different types of placenta-derived cells, they are unable to resemble the placenta-
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42 178 specific structure and functions. To overcome these problems, Ji Soo Lee et al. created,
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44 179 in 2016, a placental organ culture system through the development of a ‘placenta on a
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46 180 chip’ microdevice, which included two polydimethylsiloxane (PDMS) microfluidic
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48 181 channels divided by a membrane. To resemble in this model the placental barrier,
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50 182 HUVECs and JEG-3 trophoblast cells were cultured onto the opposite sides of the
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extracellular matrix membrane (ECM) to form endothelial and epithelial side by side
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184 layers. This microdevice demonstrated that it is possible to develop a microengineered
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3 185 biomimetic model that replicates the architecture and function of the placenta, and
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5 186 provides new opportunities to simulate and analyze critical physiological responses of
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7 187 the placental barrier (14).
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9 188 Despite the great utility of the in vitro models, the nature of the disease limits their use:
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189 specifically, PE implicate modifications in the behaviour and communication of fetal
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190 trophoblast cells with maternal endothelium (4) (See Figure 1 and Table 1 in
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16 191 Supplementary material file 1).
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18 192
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20 193 In vivo models of PE
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194 An ideal animal model for PE should reproduce as best as possible the complex
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195 pathogenesis and symptoms that underlie the disease, involving the appearance of
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196 maternal pregnancy high blood pressure and proteinuria, that should be resolved after
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29 197 delivery of the placenta (29). As mammals differ in the placentation process, it is
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31 198 difficult to find a model that satisfies completely these criteria. Table 2 summarizes the
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33 199 in vivo models for the study of PE and their main advantages and limitations (See Table
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35 200 2 in Supplementary material file 2).
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202 Trophoblast invasion models
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42 203 The placenta is considered to play a fundamental part in the appearance of PE; it is a
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44 204 specialized pregnancy-organ that is formed with the development of the embryo and
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46 205 fetus, and is comprised of several cell types, but a large part correspond to the
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48 206 trophoblast cells, which participate in the pregnancy-dependent uterine vascular
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50 207 remodeling to provide nutrients to the embryo and gas and waste exchange (30). In
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some species, trophoblast cells penetrate into the uterine compartment, establishing
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209 intimate relationships with the maternal vasculature (hemochorial placentation), a
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3 210 process commonly observed in some Insectivora, Rodentia, Chiroptera, Hyracoidea,
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5 211 Dasypodidae, Lagomorpha, Crocuta and Primates. It is believed that these groups are
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7 212 intimately linked to the primitive ancestral mammalian stock, conserving numerous of
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9 213 its anatomical characteristics (31). Other species exhibit minimal trophoblast invasion
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214 resulting in a segregation of maternal and trophoblast tissues. This type of placentation
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215 (epitheliochorial) is seen in domesticated animals, including pigs and ruminants (31).
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16 216 Intrauterine trophoblast cell invasion is an essential part of hemochorial placentation,
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18 217 and abnormalities in this process are a prominent feature of PE. Nowadays only rodents
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20 218 have been reported as in vivo models for the research of trophoblast invasion. Ain et al.
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22 219 (2003) generated mice and rats with IFNgamma genetic deficiency to examine the
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220 regulation, the endocrine phenotype and the invasiveness of trophoblast cells (32). In
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221 the same vein, Arroyo et al. (2005) and Geusens et al. (2008) described different in vivo
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29 222 methods using transgenic rat models, to assess endovascular trophoblast cell invasion,
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31 223 spiral artery remodeling and uteroplacental hemodynamics (33, 34). Mess et al. (2007)
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33 224 studied caviomorph placentation through the analysis of patterns of trophoblast invasion
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35 225 in guinea pigs and degus, proposing that caviomorphs are appropriate animal models for
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226 the study of trophoblast invasion since it showed be analogous to humans (35). Finally,
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Verlohren et al. (2010) treated pregnant rats with doxycycline to reduce trophoblast-
the
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228 vascular remodeling, decreasing following perfusion of the placenta. The model enables
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44 229 the assessment of abnormal vascular remodeling and trophoblast invasion in vivo to
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46 230 obtain significant understanding into PE-related mechanisms (36).
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48 231
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232 Uteroplacental ischemia models
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As a consequence of an inadequate trophoblast invasion, uteroplacental ischemia is an
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234 important initiating event in PE, is considered a key factor in its pathogenesis and leads
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3 235 to extend vasoconstriction, high blood pressure, and the maternal vascular endothelium
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5 236 dysfunction (37). The first models primarily addressed the mechanism of abruptio
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7 237 placentae in dogs (1953), rabbits (1963), rhesus monkeys (1968) and baboons (Papio
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9 238 anubis, 1974) by ligating permanently or temporarily the inferior vena cava,
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239 intercotyledonary vessels and uterine arteries in pregnancy, causing gradual high blood
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240 pressure and proteinuria, which concluded after delivery (38-41). Later Abitbol et al.
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16 241 (1977) perfected the method of abruptio placentae in rabbit, dogs and monkeys (Macaca
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For
mulatta) by ligating to a specific degree of stricture the terminal aorta, causing high
blood pressure, proteinuria, placental lesions, fetal growth restriction and damage in
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244 liver and kidney, similar to those found in human PE (42-44). The murine models for
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245 uteroplacental ischemia were developed until 1987, when Eder and MacDonald used
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246 laboratory rats (Sprague-Dawley) as an experimental model for pregnancy-induced
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29 247 systemic high blood pressure that was generated through a surgical reduction of blood
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31 248 pressure by 30–35 % of capacity (45). Later, Granger et al. (2006) developed a reduced
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33 249 uterine perfusion pressure (RUPP) model from modifying and characterizing the rat
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35 250 model of Eder and MacDonald, for the evaluation of cardiovascular-renal dysfunction
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251 as a consequence of placental ischemia (46). The oxygen imbalance could result from
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uteroplacental ischemia due to the hypoxia generated. The transcription factor hypoxia-
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253 inducible factor-1 (HIF-1) is a proficient regulator of systemic and cellular homeostatic
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44 254 response to low levels of oxygen and plays a key role in placental development. Several
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46 255 murine models, such as C57BL/6J pregnant mice have been developed to evaluate the
47
48 256 effects of systemic administration of adenovirus expressing stabilized HIF-1α on
49
50 257 pregnancy (47), CITED2-knockout C57BL/6:129 mice, a gene that prevents
51
52
258 transactivation of HIF-1α-induced genes through competing with binding of HIF-1α
53
54
259 (48), catechol-O-methyltransferase (COMT)-knockout C57BL/6J mice, a gene that
55
56
11
57
58
59
1
2
3 260 generates the HIF-1α inhibitor 2-methoxyestradiol (2-ME) (49) and pregnant
4
5 261 C57BL/6JArc mice TNF-α infused (50). These models showed elevated blood pressure,
6
7 262 proteinuria, reduced embryo and placental weights, fetal IUGR, histopathological
8
9 263 placental aberrations and glomerular endotheliosis, hallmark lesions of PE.
10
11
264
12
13
265 Models for angiogenesis study
14
15
16 266 Increasing evidence suggests that disturbances in angiogenic factor (such as placental
17
267 growth factor (PIGF) and vascular endothelial growth factor (VEGF)) signaling and
or
18
19
20 268 endothelial health can play a fundamental role in the pathogenesis of PE (51).
21
22 269 Exogenous administration of the anti-angiogenic factors soluble endoglin (sENG)
23
24
270 and/or soluble fms-like tyrosine kinase-1 (sFlt-1), results in a PE-like phenotype in
25
26
271 pregnant rats and mice (51-54). The first model was developed by Maynard et al.
27
28
29 272 (2003). They established the sFlt-1-induced rat model of PE through the injection of
30
31 273 adenovirus encoding the murine sFlt1 gene product (at 1×109 PFU) into the tail vein of
32
33 274 Sprague-Dawley rats on early second trimester (day 8 - 9 of pregnancy), resulting in
34
35 275 proteinuria, high blood pressure, and glomerular endotheliosis, the typical injuries of PE
36
37
276 (51). Venkatesha et al. (2006) intravenously administered Sprague-Dawley pregnant
38
39 9
277 rats with 2 x 10 PFU of adenovirus encoding sFlt1 (Ad.sFlt1), sEng (Ad.sEng) or
40
41
42 278 Ad.sEng + Ad.sFlt1 at day 8 or 9 of pregnancy, resulting in PE-like syndrome, while the
43
44 279 coadministration of sEng and sFlt1 amplified the symptoms, leading to severe PE
45
46 280 including HELLP syndrome and restriction of fetal growth (53). And finally Kumasawa
47
48 281 et al. (2011) incubated zona pellucida-free blastocysts collected from B6D2F1 pregnant
49
50 282 females in medium containing lentiviral vectors coding for sFlt1 (pLVhsFLT1), sEng
51
52
283
(pLV-EGFP) and/or placental growth factor (PGF) (pLV-mPGF).
53
54
55
56
12
57
58
59
1
2
3 284 The transduced blastocysts were implanted into pseudopregnant imprinting control
4
5 285 region (ICR) females, resulting in proteinuria and high blood pressure along pregnancy,
6
7 286 and the symptoms disappeared after delivery. The model recognizes candidates for PE
8
9 287 treatment such as low-dose statins and PGF (52). High levels of sEng and sFlt-1 are
10
11
288 commonly an indication of imminent PE and intrauterine growth restriction (55). Two
12
13
289 simple animal models for PE were developed by Molnár et al. (1994), who caused a
14
15
16 290 chronic inhibition of nitric oxide synthesis (NOS), a mediator of angiogenesis, in
17
18 291 pregnant rats through the continuous administration of L-nitro-arginine (a strong
19
20 292 inhibitor of NOS), producing a PE-like syndrome (56), and by Carlström et al. (2009),
21
22 293 who treated pregnant rats with Suramin (an angiogenesis inhibitor) during early
23
24
294 placentation, causing high blood pressure and placental dysfunction (57). These models
25
26
295 are useful not only for the study of angiogenesis deregulation but also the downstream
27
28
29 296 pathophysiology and treatment of PE.
30
31 297
32
33 298 Oxidative stress models
34
35 299 Placental oxidative stress plays a fundamental role in the pathogenesis of PE. It is a
36
37
300 result of increased free radicals and superoxide produced in the course of pregnancy that
38
39
301 could attack nucleic acids, proteins and lipids, generating the injury of both placental
40
41
302 cell and tissue and in some cases the complete organ. Oxidative stress promotes
42
43
44 303 maternal vascular endothelial dysfunction and induces leukocyte activation that could
45
46 304 compromise fetal growth (58). With the aim of determining if maternal disturbances
47
48 305 during pregnancy induce placental oxidative stress, Beauséjour et al. (2006) developed
49
50 306 an animal model that shows a PE-like syndrome by making sodium intake in drinking
51
52
307 water higher (0.9% or 1.8% NaCl) along the last WG in rats. Markers of oxidative stress
53
54
308 were measured in the placenta, identifying alterations in TNF-a expression, vasoactive
55
56
13
57
58
59
1
2
3 309 substances (eNOS and prostanoids) levels, total glutathione content and apoptotic index,
4
5 310 resulting in increased placental cell dysfunction and death. According to their results,
6
7 311 maternal perturbations during pregnancy may induce placental oxidative stress (58).
8
9 312
10
11
313 Immune models
12
13
314 A rigorous balance between suppression and immune tolerance is necessary for a
14
15
16 315 normal pregnancy, any disparity between pro-inflammatory and anti-inflammatory
17
18 316 chemokines and cytokines may lead to abnormal inflammation, which is usually
19
20 317 observed in PE (59). Several animal models have been established to investigate the
21
22 318 participation of the immune response in the pathogenesis of PE. One of the first models
23
24
319 was the one developed by Faas et al. (1994), who administered an ultra-low-dose
25
26
320 endotoxin (a bacterially derived hydrophobic molecule that induces the immune
27
28
29 321 response) infusion in conscious pregnant rats, resulting in a PE-like syndrome (60).
30
31 322 The major findings of several immune models have been achieved by administering
32
33 323 inflammatory cytokines to murine and non-human primate models. For example, in
34
35 324 pregnant Sprague-Dawley rats, treatment with IL-6 directly enhanced vascular
36
37
325 contraction and impaired endothelium-dependent relaxation in systemic vessels (61). In
38
39
326 baboons (Papio hamadryas), the intravenous administration of IL-10 and TNF-α in early
40
41
42 327 pregnancy led to vasoconstriction and endothelial dysfunction (62, 63). These results
43
44 328 demonstrated the usefulness of the administration of cytokines for inducing PE-like
45
46 329 symptoms in animal models for the study of PE pathogenesis.
47
48 330 As regards knockout murine models, IL-10-knockout pregnant C57BL/6 mice exposed
49
50 331 to low levels of oxygen or Toll-like receptor 3 (TLR-3) agonist polyinosinic-
51
52
332 polycytidylic acid (poly I:C) resulted in rated placental injury and proteinuria, high
53
54
333 blood pressure and systemic manifestations of renal pathology (64, 65). Pregnant TNF-α
55
56
14
57
58
59
1
2
3 334 infused C57BL/6JArc mice showed placental upregulation of TLR-3 and TLR-4
4
5 335 (molecules responding to inflammation) and PE-like syndrome (50). Chatterjee et al.
6
7 336 (2012) observed in women with PE a significantly increased level of the TLR3/7/8
8
9 337 family, which has a main participation in the activation of innate immunity,
10
11
338 hypothesizing that its activation will be enough to produce PE-like symptoms in mice.
12
13
339 They treated pregnant C57BL/6J mice with the TLR7/8 agonist CLO97, the TLR7-
14
15
16 340 specific agonist imiquimod (R-837) and the TLR3 agonist polyinosinic-polycytidylic
17
18 341 acid (poly I:C),causing PE-like syndrome (66).
19
20 342 A PE mouse model was established by Zenclussen et al. (2006) by transferring to
21
22 343 allogeneically pregnant BALB/c female mice, activated BALB/c Th1-like splenocytes,
23
24
344 during late gestation. This cell transfer only caused PE-like syndrome in pregnant
25
26
345 animals, further affecting the pregnancy outcome by increasing fetal rejection through
27
28
29 346 an inflammatory profile of uterine immune cells (67).
30
31 347 PE could be a pregnancy-induced autoimmune disorder, result of autoantibody-induced
32
33 348 AT receptor activation, a mediator of AT II (a potent vasopressor hormone) observed in
34
35 349 women with PE. This hypothesis has led to developed models in both rats and mice,
36
37
350 through the administration of anti-AT1-receptor antibodies along pregnancy inducing
38
39
351 PE-like syndrome (68, 69).
40
41
42 352 A new rat model by administering intraperitoneal low-dose cadmium chloride (CdCl2),
43
44 353 an inductor of immune abnormalities, in pregnant Wistar rats at gestational days 9–14
45
46 354 was established by Zhang et al. (2016); in their model, PE-like syndrome was observed
47
48 355 (70).
49
50
356
51
52
357 Others
53
54
55
56
15
57
58
59
1
2
3 358 Arginine vasopressin (AVP) is a hormone that acts on the kidney as antidiuretic
4
5 359 controlling the fluid balance, and also increases the arterial blood pressure through
6
7 360 vasoconstriction of the peripheral vessels. Santillan et al. (2014) developed a novel and
8
9 361 clinically relevant model of PE through the administration of a chronic infusion of AVP
10
11
362 along pregnancy of C57BL/6J mice, being enough to phenocopy PE (71).
12
13
363 Spontaneous animal models of PE have been discovered. Guinea pigs and patas
14
15
16 364 monkeys were the first inbred animal model reported that spontaneously generates a
17
18 365 syndrome that present a close similarity to PE (72, 73). Recently, spontaneous murine
19
20 366 models have been described: The BPH/5 has borderline high blood pressure before
21
22 367 pregnancy, being used to study early feto-placental aberrations prior to the appearance
23
24
368 of maternal disease (74, 75), and the Dahl salt-sensitive rat, a genetic and spontaneous
25
26
369 model of PE, exhibiting a phenotype consistent with several of the features observed in
27
28
29 370 human PE, such as high blood pressure and kidney disease, although it doesn’t exhibit
30
31 371 decreasing in uterine artery resistance along late pregnancy (76).
32
33 372 Thus, although in vivo studies continue to be necessary, the animal models described
34
35 373 above improve our understanding of the pathogenesis of PE and lead to the
36
37
374 identification and testing of new therapeutic targets for its treatment (See Figure 2 and
38
39
375 Table 2 in Supplementary material file 2).
40
41
42 376
43
44 377 In silico models of PE
45
46 378 PE displays system behaviors that are not easily anticipated, involving numerous and
47
48 379 tightly controlled molecular interactions that cannot be comprehended if the biological
49
50 380 molecules are treated individually, rather than considering them as an integrated system.
51
52
381 The dependence on only employing in vitro and in vivo models to study PE is
53
54
382 consequently not enough and the investigation of molecular interactions in detail is
55
56
16
57
58
59
1
2
3 383 required in order to dissect the mechanisms of the etiology, pathophysiology and
4
5 384 progression of the disease in humans.
6
7 385 Several mathematical and computational strategies have been commonly used to model
8
9 386 gene prioritization, protein-protein interaction network analysis, metabolic network
10
11
387 behaviour, the genetics of PE and the rating of women with normal, hypertensive and
12
13
388 preeclamptic pregnancy in distinct WG, and to predict the development of PE. These
14
15
16 389 include co-expression network construction, metabolic pathway analysis, genetic
17
390 algorithms, discriminant analysis classification methods, linear regression, multivariate
or
18
19
20 391 logistic regression, modular and node analysis and artificial neural networks (See Figure
21
22 392 3 and Table 3 in Supplementary material file 3).
23
24
393 Logistic regression is a popular and widely used analysis to build multifactorial models
25
26
394 to predict the development of a disease. In PE, several researchers have investigated the
27
28
29 395 utility of clinical variables, maternal characteristics, and biophysical and biochemical
30
31 396 markers obtained early during gestation, to develop models for predicting PE
32
33 397 (occurrence and severity) (77-84).
34
35 398 The variables that have been modeled includes maternal age, body mass index (BMI),
36
37
399 height, parity, blood pressure, hematocrit count, smoking, previous miscarriage, family
38
39
400 history of high blood pressure, ultrasound variables
mean arterial
such
pressure
as
40
41
42 401 (MAP) and uterine artery pulsatility index (PI) (85-88), first-trimester urine and serum
43
44 402 metabolomic profiles (89), and biochemical markers such as maternal plasma or serum
45
46 403 levels of placental protein-13, PGF, pregnancy-associated plasma protein-A, P-selectin,
47
48 404 pentraxin-3, activin-A, inhibin-A and sENG (90). The prediction efficacy of each model
49
50 405 may be compared considering the specificity and sensitivity values and/or with the area
51
52
406 under the curve.
53
54
55
56
17
57
58
59
1
2
3 407 Several significant advances have been promoted in cognitive science by the use of
4
5 408 economical computer simulations, specifically with the development of artificial neural
6
7 409 networks (ANNs), created by the logician Walter Pitts and the neurophysiologist
8
9 410 Warren McCulloch in 1943 (91) as a potential alternative to linear regression,
10
11
411 multivariate logistic regression and other conventional statistical analysis. ANNs are a
12
13
412 group of statistical learning models inspired by the network of neurons in a brain,
14
15
16 413 integrated by interconnected neurons (processing elements) functioning simultaneously
17
18 414 to resolve specific problems (92). The networks can be adjusted based on experience,
19
20 415 making them adaptive to inputs and able of learning, with the notable ability to infer
21
22 416 meaning from imprecise or complex data that can be used to identify trends and
23
24
417 discover profiles that are too difficult to be recognized by either humans or other
25
26
418 computer techniques (92).
27
28
29 419 In PE, ANNs have been used as a prediction and classification model. Mello et al.
30
31 420 (2001) applied an ANN to a group of laboratory and clinical data (ferritin, iron,
32
33 421 haematocrit, total proteins, uric acid, creatinine and urea) obtained at 16 and 20 WG to
34
35 422 evaluate the efficacy in predicting the development of PE in high-risk pregnant women.
36
37
423 Compared with a previous multivariate logistic regression approach, the ANN showed
38
39
424
high sensitivity (86.2 vs 79.3 %), specificity (95.4 vs 97.7 %), and positive (86.2 vs
40
41
425 92%) and negative predictive values (95.5 vs 93.4 %), representing an alternative
42
43
44 426 predictive model that can be performed in early pregnancy (16–20 WG), and considered
45
46 427 a tool for primary prevention, breaking off the disease process prior the clinical onset of
47
48 428 an overt disease (93). Tejera E et al. (2011) constructed a model for classifying women
49
50 429 with normal, hypertensive and preeclamptic pregnancy in distinct WG employing blood
51
52
pressure measurements, maternal history and maternal heart rate variability (HRV)
430
53
54
431
indexes. The obtained results revealed sensitivity for PE of around 80% and an even
55
56 18
57
58
59
1
2
3 432 higher percentage for hypertensive and normal pregnancy groups. Otherwise, specificity
4
5 433 in identifying PE women was approximately 85–90 %. These results show that the
6
7 434 combination of an ANN with HRV indexes could be useful in the characterization and
8
9 435 study of pregnancy (94).
10
11
436
12
13
437 Conclusion
14
15
16 438 Despite the great technological developments in health sciences, current in vitro, in vivo
17
18 439 and in silico models still have limitations in recapitulating all the molecular and clinical
19
20 440 aspects of PE. The fact that the etiology of PE remains controversial, and the clinical
21
22 441 manifestation of the disease presents great heterogeneity, differing from early to late
23
24
442 onset of PE and from mild to severe forms of the disease, makes the study of PE a big
25
26
27
28
29
30
443
444 r
experimental challenge. Although PE has been complex to study in humans due to
difficulties in the delayed appearance of the clinical manifestation, the impossibility of
31 445 obtaining placental tissues from early stages of gestation and the ethical and technical
32
33 446 considerations that preclude the performance of human experiments, human studies are
34
35 447 still the gold standard in interpreting the epidemiology and clinical implications of the
36
37
448 disease. Therefore, the current model systems offer many advantages in overcoming the
38
39
449
research limitations imposed by human studies, and have contributed significantly to
40
41
450 understanding the clinical correlations between genetic, molecular biologic,
42
43
44 451 biochemical, physiologic and pathologic analysis, giving great insights into the disease,
45
46 452 and in some cases, leading to randomized controlled trials being conducted in humans.
47
48 453 Despite the potential of these models to enable comprehension of the pathogenesis of
49
50 454 PE and to test preventative and therapeutic strategies in its management, additional
51
52
research is needed to develop new model systems that lead to the provision of helpful
455
53
54
456 information on how to prevent placental dysfunction in PE.
55
56
19
57
58
59
1
2
3 457
4
5 458 Authors’ contributions
6
7 459 All authors participated in the design, review, and editing of this manuscript. MFML
8
9 460 and GVI wrote the manuscript.
10
11
461
12
13 462 Funding
14
15
16 463 This study was funded in part by CONACyT: INFR-2014-01-225520, INFR-2015-01-
17
18 464 254106, PDCPN- 2015-01-63, SEP-CONACYT-CB-2015-258316 and
19
20 465 SS/IMSS/ISSSTE-CONACYT-2016-01-273144.
21
22 466
23
24
467 Declaration of conflict of interest
25
26
468 The authors declare that they have no competing interests.
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3 839 115. Tejera E, Bernardes J, Rebelo I. Preeclampsia: a bioinformatics approach through
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5 840 protein-protein interaction networks analysis. BMC systems biology. 2012;6:97.
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7 841 116. Triche EW, Uzun A, DeWan AT, Kurihara I, Liu J, Occhiogrosso R, Shen B,
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9 842 Parker J, Padbury JF. Bioinformatic approach to the genetics of preeclampsia.
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843 Obstetrics and gynecology. 2014;123(6):1155-61.
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Title
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6 “Current model systems for the study of preeclampsia”
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Journal name: Experimental Biology and Medicine
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11
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13 Authors
14
15 Martinez-Fierro ML, Hernández-Delgadillo GP, Flores-Morales V, Cardenas-Vargas E, Mercado-Reyes M, Rodriguez-Sanchez IP,
16 Delgado-Enciso I, Galván-Tejada CE, Galván-Tejada JI, Celaya-Padilla JM, Garza-Veloz I †.
17
18
19
†
20 Corresponding author
21
22
Molecular Medicine Laboratory, Unidad Academica de Medicina Humana y C.S.
23
Universidad Autonoma de Zacatecas.
24
25 Carretera Zacatecas-Guadalajara Km.6. Ejido la Escondida, C.P. 98160,
26
27 Zacatecas, Mexico
28 E-mail address: idaliagv@uaz.edu.mx
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Table 1. Preeclampsia in vitro research model systems
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6
Type Models Method Species Description Advantages Disadvantages References
7
8 Cell - To understand Trophoblast cell Human Cell cultures of Isolated primary - Although a panel of markers (11, 17,
culture trophoblast cell lines: trophoblast. trophoblast no and phenotypic criteria have 95)
9
biology, - ED27 longer proliferates been established to characterize
10
immunology, - ED31 in culture. Thus, the cell lines so they can be
11
endocrine function - ED77 only short-term considered a trophoblast cell,
12 - HP-A1
and placental cultures can be very few of them have been
13 development. - HP-A2 performed with evaluated for expression of
14 - To assess the - HP-W1 primary cells. these specific factors, probably
15 effect of - HT Therefore, due to the availability of well-
16 differentiation and - HT-116 respective cell lines characterized reagents for
17 fusion on the - HTR-8 have been evaluation.
18 expression and - HTR-8/Svneo developed to - The methods employed to
19 release of a PE - IST-1 overcome the extend lifespan (transfection or
20 marker. - NHT handicap of spontaneous
21 - To study the - NPC missing immortalization/transformation)
22 regulation of - RSVT-2 proliferation of alter regulation of cell division
23 trophoblast - RSVT2/C primary and may impact on
24 apoptosis and - SGHPL-4 trophoblasts in differentiated functions and
25 placental - SGHPL-5 culture. gene expression not usually
26 development under - SGHPL-6 observed in trophoblast cells in
27 hypoxic conditions. - SGHPL-7 vivo or in primary culture.
28 - SPA-26+7 lines
29 - TCL-1
30 - TL
31
Malignant
32
choriocarcinoma
33
cell lines:
34
- AC1
35 - AC1-1
36 - AC1-5
37 - AC1-9
38 - AC-1M32
39 - AC-1M46
40
41
42
43
44
46
47
1
2
3
4 - AC-1M59
5 - AC-1M81
6 - AC-1M88
7 - BeWo
8 - BeWo MC-1
9 - BeWo MC-2
10 - JAR
11 - JEG
12
13 Embryonal lines
14 with trophoblast
15 differentiation:
16 - H9
17 - HT-H
18 - NCC-EC-3
19 - NCCIT
- NCR-G3
20
21 To determine: Normal primary Human HUVECs cultured - This cell line is - HUVECs are limited to 10–15 (96-100)
22 - Oxidative stress. umbilical vein with ideal for evaluating population doublings.
- Effects of endothelial cells syncytiotrophoblast- immune response, Continued passaging beyond 15
23
syncytiotrophoblast- (HUVECs). derived wound healing, doublings (4–5 passages after
24
derived microparticles, cellular response to receipt) may result in decreased
25
microparticles in the serum, plasma, viral or bacterial growth rates and loss of
26 maternal molecules or drugs infection, oxidative biological responsiveness.
27 circulation, serum for the evaluation of stress,
28 or plasma from proliferation, angiogenesis,
29 patients with PE on apoptosis rates of the arteriolosclerosis,
30 proliferation, injury HUVECs and drug screening and
31 and apoptosis of therapeutic tubule formation,
32 human umbilical properties. mechanisms
33 vein endothelial implicated in PE.
34 cells.
35 - Effects of PE
36 biomarkers or
37 molecules with
38 therapeutic
39 potentials.
40
41
42
43
44
46
47
1
2
3
4 To evaluate: - Connexins and Mouse - Generation of Placentation in Generation of trophoblast stem (101, 102)
5 - Basic mechanisms trophoblast cell trophoblast stem cell mice involves cells from knockout blastocysts
6 of gene regulation lineage lines from connexin- similar cell seems to be accompanied by
7 in trophoblast cell development. deficient mice. This biological events to more methodological problems,
8 lineage - Placental vascular may be used to humans, without especially if the genes that are
9 differentiation. development elucidate the the ethical deleted alter the differentiation
10 - Placenta through ubiquitin mechanism of problems of pathway.
11 development. ligase Ankyrin differentiation and the abortion and the
12 - Vascularization of repeat. role of genes and cell availability of
13 the placenta. types in the sufficient tissues
14 development of the for research. One
15 placenta. major point is that
16 - Differentiation of the most important
17 embryonic stem cell steps of trophoblast
18 to vascular lineage differentiation
19 through ubiquitin occur within the
20 ligase Ankyrin first weeks of
21 repeats. gestation.
22 - Human - Cytotrophoblast Human - Generation of - First human - To acquire the physiology of (103)
23 placentation and its stem (CTBS) cell cytotrophoblast cell CTBS cell lines to CTBS cells, spheroidal
potential in cell lines derived from lines isolated from be derived from trophoblast bodies and matrigel
24
therapy human embryonic embryoid bodies and human embryonic are required to resemble the
25
applications. stem cells. selected for stem cells and then implanting embryo and mimic
26
- Invasive trophoblast maintained the endometrial deciduas,
27 enrichment by rounds independently respectively.
implantation events.
28 of cellular without feeder
29 aggregation and cells.
30 disaggregation. - Differ from
31 immortalized
32 placental lines in
33 that they have
34 multipotent
35 capacity to
36 differentiate to
37 various trophoblast
38 phenotypes
39 including
40 syncytiotrophoblast
41
42
43
44
46
47
1
2
3
4 and extravillous
5 cytotrophoblast.
6
7
8
Explants Trophoblast - First-trimester Human First-trimester - Trophoblast is - Inability to identify the (12, 19)
9 invasion villous explants (to floating villi in conditioned by co- activities of individual cell
10 study contact with a culture with types.
11 postimplantation permissive appropriate cells. - Drugs, oxygen, infections,
12 events, early stages extracellular matrix nutrients, hormones,
13 of placentation and substrate stimulates xenobiotics or cytokines can
14 cytotrophoblast cytotrophoblast affect tissue functions and
15 invasion). proliferation and its survival.
16 column formation.
17 - Trans-filter Human, Purified primary first- It can be used - Minimal contamination by (19, 104)
18 cytotrophoblast mouse trimester quantitatively, connective tissue cells may
19 migration (to study cytotrophoblast cell providing good migrate or proliferate faster
20 the phase of suspension. quality control. than trophoblast during the
21 migration when assay period.
22 single cells move - Cytotrophoblasts are not
23 through the unequivocally identifiable by
24 decidual or morphological criteria.
25 myometrial
26 environment)
27 Trophoblast Spiral artery Human Fluorescently labeled It is useful for Difficult to manipulate arteries (105)
28 invasion invasion and trophoblasts (either studies that lack and handle the co-culture.
29 of spiral arteries remodeling, primary first- suitable models
30 developed using trimester extravillous directly examining
31 spiral artery trophoblasts or cellular interactions
explants, an extravillous during invasion.
32
extravillous trophoblast cell line)
33
trophoblast cell are seeded on top of
34
lines and primary spiral artery segments
35 cytotrophoblasts. (obtained from
36 uterine biopsies at
37 Caesarean section)
38 embedded in fibrin
39 gels (to study
40
41
42
43
44
46
47
1
2
3
4 interstitial invasion)
5 or perfused into the
6 lumen of arteries (to
7 study endovascular
8 invasion). Both
9 interstitial and
10 endovascular
11 interactions/invasion
12 can be detected and
13 immunohistochemical
14 analyses carried out.
15 Probe preventive Extravillous Human Chorion from term - Although the - It has been reported that these (106)
16 and therapeutic trophoblast. placentas was model was kinds of cells are only partly
17 agents for PE digested and developed to study involved in the release of any of
18 extravillous thrombophilia, it is the predictive biomarkers
19 trophoblast isolated, useful to apply in available today.
20 then it was used to the study of PE. - They no longer proliferate in
21 investigate the effect - It is a useful tool culture. Hence, only short-term
22 of unfractionated, for demonstrating cultures for some days can be
23 low-molecular-weight any effect of performed. At the same time
24 heparin and aspirin putative these cells spontaneously
on in vitro therapeutics on syncytialize in culture and thus
25
extravillous extravillous may be of use to study the
26
trophoblast trophoblast, release of syncytial fragments
27
differentiation. especially during and factors in vitro.
28 very early
29 placentation since
30 defects in
31 extravillous
32 trophoblast
33 function could play
34 an important role in
35 the etiology of
36 pregnancy
37 disorders such as
38 PE.
39 Oxidative stress Villous trophoblast Human Term placenta was This culture - They no longer proliferate in (20, 100)
40 and amniotic tissue digested and villous represents a useful culture. Hence, only short-term
41
42
43
44
46
47
1
2
3
4 cultures. cytotrophoblasts in vitro model cultures for some days can be
5 isolated, then they system to assess performed.
6 were used to evaluate drug effectiveness. - At the same time these cells
7 the effects of spontaneously syncytialize in
8 antioxidant vitamins culture and thus may be of use
9 C and E on to study the release of syncytial
10 trophoblast in culture. fragments and factors in vitro.
11 Villous and amniotic
12 tissue cultures and
13 stimulation with 4-
14 hydroxy-nonenal,
15 natrium fluoride and
16 xanthine/xanthine
17 oxidase.
18 - Placental Villous explants. Human - First- and third- Useful to study - Deficient availability of fresh (107, 108)
19 metabolism and trimester human various facets of material for explant cultures.
20 syncytiotrophoblast placental explants the materno-fetal - Villous explants are not
21 death. were cultured with interface, including regularly stored frozen. Hence,
22 - Effect of anti- antiphospholipid analysis of placental tissues can only be
23 hypertensive drugs antibodies, and placental endocrine used directly after delivery, and
on placental several metabolites function, explant cultures using tissues
24
hormones and with important roles metabolism, from a single placenta cannot
25
angiogenic protein in cell death transport and to be repeated at a later date. So to
26
synthesis, known to regulatory pathways dissect cellular overcome this problem a larger
27 were analyzed. processes such as number of villous explants
be altered in PE.
28 - Placental villous proliferation, derived from a single placenta
29 explants from late differentiation, could be explored.
30 onset PE were apoptosis and
31 cultured at 20% syncytial fusion.
32 oxygen with variable
33 doses of anti-
34 hypertensive drugs.
35 The levels of
36 different molecules
37 were measured in
38 explant culture
39 media.
40 Co- Immune response - Macrophage- Human - Isolation and cell None of the co- - The type of cytokines (13, 21-24)
41
42
43
44
46
47
1
2
3
4 cultures trophoblast culture of cultured cells affect produced by a macrophage
5 interactions. macrophages, proliferation, depends on its activation state.
6 - Trophoblast- primary trophoblasts, apoptosis and cell - The type of effect in the
7 derived cell line peripheral blood column formation. inflammatory response depends
8 co-cultured with mononuclear cell, upon the state of trophoblast.
9 peripheral blood neutrophils and - The co-cultures need a
10 mononuclear cells natural killer cells. scaffold that allows a 3D
11 under hypoxic - Co-culturing of conformation leading to cell-
12 conditions. macrophages- cell interaction and column
13 - Maternal trophoblast, formation.
14 neutrophils co- trophoblast-peripheral
15 cultured with the blood mononuclear
16 syncytiotrophoblast cells, neutrophils-
17 microvillous syncytiotrophoblast
18 membranes. microvillous
Factors in plasma membranes, and
19
of PE women natural killer-villous
20
activate endothelial explants.
21
cells to produce IL- - Evaluating the co-
22 8 resulting in culture interactions.
23 transendothelial
24 migration of
25 neutrophils.
26 - Interaction
27 between natural
28 killer cells and
29 villous explants
30 from concordant
31 first-trimester
32 pregnancies co-
33 cultured in a
34 collagen model of
35 placentation.
36 Trophoblast HTR-8/SVneo Human Trophoblast - To evaluate the - These models only identified (25-27)
37 proliferation, trophoblast cells or migration and effect of each cell the maternal physical properties
38 migration, invasion trophoblast-derived interactions with line co-cultured on of the invasion.
39 and endothelial cell JEG-3 cells co- endometrial the proliferative - The difficulty in obtaining the
40 interactions. cultured with endothelial cells were and invasive samples on a regular basis also
41
42
43
44
46
47
1
2
3
4 human uterine measured using properties of the prohibited these models’
5 myometrial Transwell permeable other. widespread use.
6 microvascular support or co-cultured - To evaluate
7 endothelial cells or in matrigel. antihypertensive
8 with human and anti-
9 endometrial inflammatory drugs
10 endothelial cells that can modulate
11 into formation of the interaction
12 capillary-like between
13 cellular networks. trophoblast and
14 endothelial cells.
15 - These are 3D
16 models (cellular
17 networks) that
18 likely mimic the
19 trophoblast
20 interaction with
21 endothelium during
remodeling.
22
Cytotrophoblast Cytotrophoblast Human Transwell migration Cytotrophoblast Because placental (109)
23
invasion co-cultured with assay was used to cultured alone with immunological tolerance is
24
human uterine detect the invasive normal or regulated by many factors, this
25
spiral artery ability of preeclamptic serum in vitro model might not fully
26
smooth muscle cytotrophoblast co- was lower than represent the in vivo situation of
27 cell. cultured with human cytotrophoblast uterine spiral artery remodeling
28 uterine spiral artery cultured with in PE.
29 smooth muscle cell, human uterine
30 incubated with spiral artery smooth
31 normal or muscle cells.
32 preeclamptic serum.
33 Placental Placenta biology Placenta-on-a- Human A ‘Placenta-on-a- - Replicates the - Although the microfluidic (14)
34 organ Chip. Chip’ is a architecture and culture system provides a
35 culture microsystem that function of the greater physiological cell
36 consists of two placenta. culture environment than
37 polydimethylsiloxane - Provides new conventional static cultures, the
38 microfluidic channels opportunities to levels of shear stress generated
39 separated by a thin simulate and in the model are substantially
40 extracellular matrix analyze critical lower than those in fetal
41
42
43
44
46
47
1
2
3
4 membrane. To physiological capillaries. This is mainly due
5 reproduce the responses of the to the large size of the cell
6 placental barrier, placental barrier. culture chambers.
7 human trophoblasts - It is a low-cost - It has only been proved by
8 (JEG-3) and human experimental employing the JEG-3 cell line
9 umbilical vein platform with a and HUVECs to represent
10 endothelial cells broad range of trophoblast and endothelial
11 (HUVECs) are applications. cells, respectively. It could be
12 seeded on the - Overcomes the better if it employs primary
13 opposite sides of the limitations that the human trophoblasts and fetal
14 membrane and current in vitro capillary endothelial cells.
15 cultured under models have in
16 dynamic flow recapitulating the
17 conditions to form organ-specific
18 confluent epithelial structure and key
19 and endothelial layers physiological
20 in close apposition. functions of the
21 placenta.
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
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4
Title
5
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10
11
12
13 Authors
14
17
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19
†
21
22
23
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26
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Table 2. Preeclampsia in vivo research model systems
5
6
Models Method Species Description Advantages Disadvantages References
7
8 Trophoblast cell Placental bed Human Biopsies from the Small tissue - Specimens acquired (110-113)
9 Invasion histological sections placental bed for samples are needed almost exclusively after
for identification of histological evaluation for the study (0.5 to delivery.
10
structural changes in of the uterine 1 cm). - Marked variation in the
11
uterine blood vasculature. Obtained patterns of interstitial and
12
vessels, disturbed from: endovascular trophoblast
13 by invading - Delivered Placentas invasion and in the
14 trophoblastic cells - Hysterectomy associated modifications of
15 in complicated Specimens the spiral arteries from the
16 pregnancies. - Caesarean Section center to the margins of the
17 - Biopsies Under placental bed.
18 Ultrasound Guidance. It is a challenge to
19 extrapolate from the
20 findings in small tissue
21 fragments to the whole
22 placental bed.
23 Invasion may be irregular
24 and vasculopathies may
25 occur focally.
26 Analysis of the Rat, mouse Sprague-Dawley, CD- The rat and mouse The phenotype of invasive (32)
27 endocrine 1 mice, Tgε26 mice model systems rodent trophoblast cells is
28 phenotype of and C57BL/6 mice, exhibit features distinct from phenotypes
29 invasive trophoblast IFNγ and IFNγ shared with for intraplacental
30 cells, and aspects of receptor null mutant, primates and trophoblast cell lineages.
31 the regulation of were used as model to expand the
32 trophoblast cell investigate: experimental
33 invasion during - Trophoblast invasion repertoire for
pregnancy of in rats and mice. studying
34
rodents with genetic - The endocrine trophoblast cell
35
deficiency of INFγ. phenotype of these invasion.
36
invading trophoblast
37
cells, and the potential
38 modulatory roles of
39 NK cells and the NK
40
41
42
43
44
46
47
1
2
3
4 cell product IFNγ in
5 the regulation of
6 trophoblast invasion.
7 Evaluate the depth Rat - Sprague-Dawley rats This technique The techniques are most (33, 34)
8 of endovascular harboring the human should facilitate the effective when performed
9 trophoblast invasion renin (hRen) or human discovery of in conjunction with
10 and associated angiotensinogen gene endogenous qualitative techniques used
11 remodeling of spiral (hAogen). regulatory for the in situ identification
12 arteries in a - Fischer 344 R26- mechanisms and localization of invasive
13 transgenic model of hAP rats that possess a controlling trophoblast cells.
14 PE in rats. transgene consisting of trophoblast cell
15 a Rosa 26 promoter invasion and should
16 driving the expression represent an
17 of a heat-stable human effective method of
18 placental AP. testing the impact
19 of various
20 environmental
21 stressors on an
22 essential part of
hemochorial
23
placentation.
24
The origin, Guinea pig, Histology and The patterns of Not all intrauterine BrdU (35)
25
migration routes and degus immunohistochemistry trophoblast invasion injections resulted in BrdU-
26
kinetics of invasive were performed on in caviomorphs are staining of placental
27 trophoblast cells placentas from mid- analogous to the trophoblast, suggesting that
28 were examined in gestational stages from situation in humans, not all intrauterine
29 two caviomorph pregnant guinea pigs suggesting that compartments are equally
30 species. and degus treated with these rodents are suitable injection sites for
31 3 doses of BrdU (an in appropriate animal this tracer.
32 vivo marker for models for the
33 proliferation and for study of the
34 tracing of migration dynamics of
35 routes in the placenta) trophoblast
36 injected invasion.
37 intraperitoneally.
38 Reduction of Rat Preeclamptic and The model allows The doxycycline is (36)
39 placental perfusion pregnant control the study of teratogenic.
40 through the Sprague-Dawley rats dysregulated
41
42
43
44
46
47
1
2
3
4 inhibition of were treated with trophoblast invasion
5 trophoblast-induced doxycycline from and vascular
6 spiral artery gestational day 12 remodeling in vivo
7 remodeling in until day 18. to gain important
8 pregnant rats. insights into PE-
9 related mechanisms.
10 Uteroplacental Produce placental Dog, rabbit, Abruptio placentae by Suppression of - Fibrinoid degeneration (38-41)
11 ischemia abruption by rhesus ligating permanently uteroplacental and aneurysmal dilatation
12 reducing its monkeys, or temporarily the blood flow leads to were produced in the
13 perfusion. baboons inferior vena cava, a hypertensive state decidual vessels.
14 intercotyledonary that closely - The vessels are often
15 vessels or uterine resembles destroyed by the process.
16 arteries in pregnancy, PE in women. - The hypertensive state
17 causing progressive persisted until the
18 hypertension and postpartum period.
19 proteinuria, which
20 ceased after delivery.
21 Partially occluding Dog, rabbit, Ligating the terminal Reductions in - The condition may lead to (42-44)
22 the uteroplacental monkey aorta to a specific uteroplacental fetal death.
23 blood flow of degree of stricture, blood flow lead to a - Appropriate clip size and
24 pregnant animals causing placental hypertensive state the ideal gestational time
resulted in lesions, hypertension, that closely for reducing uterine
25
hypertension. proteinuria, fetal resembles perfusion pressure were
26
growth restriction and PE in women. undetermined.
27
changes in liver and - The degree of aortic
28 kidney. constriction was
29 imprecisely controlled.
30 Produce the Rat Develop a reduced - Reductions in The proteinuria response (45, 46)
31 Reduced Uterine uterine perfusion uteroplacental was variable in the pregnant
32 Perfusion Pressure pressure (RUPP) blood flow lead to a rats with reduction of
33 (RUPP) model for model by reducing hypertensive state uterine perfusion pressure.
34 studying uterine perfusion that closely
35 cardiovascular-renal pressure in gravid resembles PE in
36 dysfunction in Sprague-Dawley rats women.
37 response to by placing a silver clip - Appropriate clip
38 placental ischemia. around the aorta below size and the ideal
39 the renal arteries and gestational time for
40 on both the right and reducing uterine
41
42
43
44
46
47
1
2
3
4 left uterine arcade at perfusion pressure
5 the ovarian end just were determined.
6 before the first - The degree of
7 segmental artery. aortic constriction
8 was precisely
9 controlled.
10 Effects of hypoxia- Mouse - C57BL/6J mice with These models - Immune response to (47-50)
11 inducible factor- systemic showed PE-like adenoviral vector systems
12 1alpha (HIF-1α) administration of syndrome. can cause severe
13 expression on adenovirus expressing complications for the
14 pregnant mice. HIF-1α, animal model.
15 - CITED2-knockout - Proteinuria was present
16 C57BL/6:129 mice, both in cases and in control
17 - Catechol-O- groups.
18 methyltransferase
19 (COMT)-knockout
20 C57BL/6J mice,
21 - Pregnant
22 C57BL/6JArc mice
23 TNF-α infused.
Angiogenesis Administration of Mouse, rat Overexpression of Models mimic - Immune response to (51-54)
24
soluble sFlt-1 and angiogenic regulator multiple aspects of adenoviral and lentiviral
25
sEng. factors such as sFlt-1 PE (based on vector systems not only
26
and sEng in pregnant current ACOG impedes the delivery of
27
mice and rats results in criteria), including genes to target cells but can
28 a PE-like phenotype. development of cause severe complications
29 HELLP. for the animal model.
30 - The teratogenicity of
31 statins is an obstacle to its
32 use.
33 Prolonged blockade Rat L-nitro-arginine (a Chronic inhibition L-nitro-arginine is a (56)
34 of nitric oxide potent inhibitor of of nitric oxide nonspecific vasoconstrictor
35 synthesis. nitric oxide synthase) synthesis in that could inhibit the
36 was infused pregnant rats leads coronary vascular
37 continuously in to sustained responses.
38 pregnant rats. hypertension,
39 proteinuria,
40 thrombocytopenia
41
42
43
44
46
47
1
2
3
4 and intrauterine
5 growth retardation,
6 providing a simple
7 animal model for
8 PE.
9 Angiogenesis Rat Administration of the The inhibition of Suramin is a nonspecific (57)
10 inhibition during angiogenesis inhibitor uterine vasoconstrictor, with severe
11 early placentation. Suramin during early angiogenesis side effects.
12 placentation of increases maternal
13 Sprague-Dawley rats. blood pressure and
14 compromises fetal
15 and placental
16 development.
17 Oxidative stress Salted-water intake. Rat Increasing sodium Maternal insult Early stages of gestations (58)
18 intake (0.9% or 1.8% during gestation were not evaluated.
19 NaCl in drinking induced an
20 water) during the last imbalance in the
21 week of gestation in oxidative
22 the Sprague-Dawley environment in the
23 pregnant rats. placenta favoring
24 oxidation, and
provides an animal
25
model for studying
26
the maternal
27
manifestation of
28
PE.
29 Immune response Rat (60)
Ultra-low-dose Administration of an Histopathologic and There is no evidence that
30 endotoxin infusion ultra-low-dose clinical events human PE is caused by
31 in pregnant rats. endotoxin infusion in mimic predominant endotoxin.
32 conscious pregnant features of human
33 rats. PE.
34 Administration of Rat, mouse, - Sprague-Dawley rats These models The vascular endothelium (50, 61-65)
35 inflammatory baboons treated with IL-6, showed PE-like releases other vasodilator
36 cytokines. - Papio hamadryas syndrome and substances that could
37 treated with IL-10 and placental changes in influence the inflammatory
38 TNF-α, molecules cytokine activity.
39 - IL-10-knockout responding to
40 pregnant C57BL/6 inflammation.
41
42
43
44
46
47
1
2
3
4 mice exposed to low
5 levels of oxygen or
6 Toll-like receptor 3,
7 - And pregnant
8 C57BL/6JArc mice
9 TNF-α infused.
10 Placental Toll-Like Mouse Treated pregnant Treatment of mice Placental activation of (66)
11 Receptor 3 and C57BL/6J mice with with poly I:C, R- LR3/7/8 by dsRNA and
12 Toll-Like Receptor the TLR3 agonist 837, or CLO97 ssRNA could arise from
13 7/8 activation. polyinosinic- caused pregnancy- latent viruses, viruses
14 polycytidylic acid dependent acquired during gestation,
15 (poly I:C), the TLR7- hypertension, as well as excessive cellular
16 specific agonist endothelial necrosis/apoptosis resulting
17 imiquimod (R-837) dysfunction, from aberrant implantation,
18 and the TLR7/8 splenomegaly and placentation, placental
19 agonist CLO97 placental hypoxia and/or trophoblast
20 causing PE-like inflammation. invasion.
21 syndrome.
22 Adoptive cell Mouse Adoptively Cell transfer Adoptive cell transfer (67)
23 transfer in pregnant transferring activated provoked PE further affected pregnancy
24 mice. BALB/c Th1-like symptoms outcome by increasing fetal
splenocytes into (increased blood rejection through an
25
allogeneically pressure and inflammatory profile of
26
pregnant BALB/c glomerulonephritis uterine immune cells.
27
female mice during accompanied by
28
late gestation. proteinuria).
29 Rat, Mouse (68, 69)
Effect of Infusion of activating - Key features of - No progression to
30 angiotensin receptor antibodies against PE, placental eclampsia.
31 agonistic angiotensin II type 1 abnormalities and - Not all women with PE
32 autoantibodies in receptor (AT(1)-AB) small fetus size have antibodies.
33 pregnant rodents. alone or combined appeared in - The effects could be
34 with angiotensin II pregnant rodents prevented by co-injection
35 into pregnant Sprague- after injection with with losartan, an AT (1)
36 Dawley and C57BL/6J AT(1) agonistic receptor antagonist, or by
37 pregnant mice induced autoantibodies. an antibody neutralizing
38 PE-like syndrome. seven-amino-acid epitope
39 peptide.
40 Low-dose cadmium Rat Intraperitoneal Key features of PE Pregnant women are more (70)
41
42
43
44
46
47
1
2
3
4 chloride (CdCl2) administration of appeared in vulnerable to Cd because of
5 infusion in pregnant cadmium chloride pregnant rats after the greatly increased
6 rats. (CdCl2) in Wistar rats the administration absorption and retention of
7 on gestational days 9– of low dose of Cd caused by nutritional
8 14. CdCl2. deficiencies during
9 pregnancy.
10 Other Chronic Mouse Chronic infusion of AVP constitutes a AVP is known to be (71)
11 administration of AVP in C57BL/6J novel very early affected and is an effector
12 arginine vasopressin mice during pregnancy human pregnancy of multiple immune cells.
13 (AVP). is sufficient to biomarker and
14 phenocopy PE. clinically relevant
15 mouse model of PE.
16 Spontaneous PE. Mouse, rat, Reports of - Might share - Cost and availability of (72-76)
17 caviomorph, spontaneous etiology with these animals are limiting.
18 patas preeclamptic human PE. - Disease has not been
19 monkey. symptoms in BPH/5 - Disease severity is characterized based on the
20 mice, Dahl salt- similar to that seen current diagnostic criteria
21 sensitive S and in humans. for humans (ACOG, 2013).
22 spontaneously - Resembled PE in
23 hypertensive (SHR humans more
24 SHR/NHsd or SHR) closely than the
rats, guinea pigs and experimentally
25
Erythrocebus patas. induced disease in
26
other animals.
27
28
29
30
31
32
33
34
35
36
37
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40
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Title
5
7
8
9
10
11
12
13 Authors
14
17
18
19
†
21
22
23
24
26
29
30
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32
33
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2
3
4
Table 3. Preeclampsia in silico research model systems
5
6
Models Method Species Description Advantages Disadvantages References
7
8 Gene prioritization - Co-expression Human The gene prioritization - It can integrate and - Nodes located in small (114)
9 network in PE was explored, analyze a large subnetworks may report
construction. combining co- amount of relatively high closeness
10
- Modular and expression network information derived centrality values.
11
node analysis. analysis and genetic from ‘omic’ - The analysis of more
12
- Genetic algorithm optimization experimental samples than variables
13 algorithms approaches. approaches. (genes) are recommended to
14 applied in - Co-expression avoid false discoveries
15 combination with network analysis (false relevant correlations).
16 the nearest combining both
17 neighbor and modular and gene-
18 discriminant centered approaches
19 analysis are capable of
20 classification identifying genes
21 methods. significantly related
22 to PE.
23 Protein-protein - Several indexes Human A comprehensive - This methodology - Experimental validation (115)
24 interaction network of centrality were genes/proteins data set leads to the for new candidates is
25 analysis explored for hub was created by the identification of needed.
26 detection as well analysis of both public unknown - It is necessary to reduce
27 as enrichment proteomic data and interactions of the gene space applying
28 statistical analysis text mining of public proteins/genes and a other methodologies as well
29 of metabolic scientific literature. better integration of as to design new
30 pathways and metabolic pathways experimental experiences.
31 disease. and PE. - The limitation of the
32 human protein interaction
33 information suggests that
orthologous genes should
34
also be needed in order to
35
increase the protein-protein
36
interaction network,
37 covering the initial data set,
38 and to increase the
39 capabilities of the metabolic
40
41
42
43
44
46
47
1
2
3
4 pathways and disease
5 enrichment analysis.
6 Genetics of PE Cluster analysis Human To identify candidate - The gene sets - The authors found a (116, 117)
7 was used to genes and genetic presented are useful notable lack of consistency
8 aggregate variants for PE, a for: in the definition of PE in the
9 extracted genes bioinformatic 1. Analyzing literature.
10 from the approach was used to available data on - Specific, well-defined
11 published extract and organize PE. phenotypes may be critical
12 literature into genes and variants 2. Analyzing the to understanding the genetic
13 gene sets from the published genetic architecture architecture of PE, and in
14 associated with literature. of PE. the statistical power of data
15 PE. 3. Clustering of sets.
16 Gene ontology genes associated
17 was used to with PE by
18 organize this phenotype and by
19 large group of source.
20 genes into
21 ontology groups.
22 Artificial Neural Artificial neural Human - Model construction - ANN models: - ANN models: (93, 94)
23 Networks networks and for: 1. Require less 1. Has limited ability to
multivariate 1. Classification of formal statistical identify possible causal
24
logistic women with normal training to develop. relationships.
25
regression were blood pressure, high 2. Can detect 2. Requires greater
26
applied to a set of blood pressure and PE complex nonlinear computational resources.
27 clinical and relationships 3. Are prone to overfitting.
in different gestational
28 laboratory data ages using maternal between 4. Development is
29 collected at heart rate variability independent and empirical, and many
30 different weeks of indexes. dependent variables. methodological issues
31 gestation. 2. Predicting the 3. Have the ability remain to be resolved.
32 - The development of PE in to detect all possible
33 performance of consecutive interactions between
34 each model was normotensive pregnant predictor variables.
35 assessed using women at high risk of 4. Can be developed
36 receiver operator PE and intrauterine using multiple
37 characteristic fetal growth different training
38 (ROC) curves. retardation. algorithms.
39 5. Has the ability to
40 learn how to do
41
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1
2
3
4 tasks based on the
5 data given for
6 training or initial
7 experience.
8 6. Can create its
9 own organization of
10 the information it
11 receives during
12 learning time.
13 7. ANN
14 computations may
15 be carried out in
16 parallel.
17 8. Partial destruction
18 of a network leads
19 to the corresponding
20 degradation of
21 performance.
Multivariate A multivariate Human Investigate the - Logistic - Logistic regression: (77-84)
22
logistic regression logistic usefulness of several regression: 1. Requires formal
23
model regression model biological markers, 1. Is more robust. statistical training to
24
was used to clinical and standard The independent develop.
25
evaluate the laboratory parameters variables don’t have 2. Requires much more data
26 potential of for the individual to achieve stable,
to be normally
27 biological prediction of PE, after distributed, or have meaningful results. For
28 markers, standard 10th week of equal variance in logistic regression, at least
29 laboratory gestation. each group. 50 data points per predictor
30 parameters, and 2. Does not assume are necessary to achieve
31 biochemical and a linear relationship stable results.
32 clinical factors to between the 3. If wrong independent
33 predict the variables. variables are included, the
34 occurrence of PE. 3. Can add explicit model will have little to no
35 interaction and predictive value.
36 power terms. 4. Cannot predict
37 4. Distributed error continuous outcomes.
38 terms are not 5. Requires each data point
39 assumed. to be independent of all
40 other data points.
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2
3
4 6. Is vulnerable to
5 overconfidence.
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Current model systems for the study of preeclampsia

Article in Experimental Biology and Medicine · February 2018

Margarita L Martinez-Fierro Virginia Flores-Morales

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Iram Pablo Rodriguez-Sanchez Ivan Delgado-Enciso

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Current model systems for the study of preeclampsia

Journal: Experimental Biology and Medicine

Date Submitted by the Author: 29-Dec-2017

r Investigación e Innovación Tecnológica Industrial (CIITI), Universidad

myometrial part at 16 – 18 WG (second invasion), invading the arterial wall and

employed to model gene prioritization, protein-protein interaction network analysis,

utilization of these cell lines, the International Federation of Placenta Associations

difficulties in the delayed appearance of the clinical manifestation, the impossibility of

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