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Altered expression of G1/S phase cell cycle regulators in placental mesenchymal stromal cells derived from preeclamptic pregnancies with fetal-placental compromise.

ABSTRACT: Herein, we evaluated whether Placental Mesenchymal Stromal Cells (PDMSCs) derived from normal and Preeclamptic (PE) placentae presented differences in the expression of G1/S-phase regulators p16INK4A, p18INK4C, CDK4 and CDK6. Finally, we investigated normal and PE-PDMSCs paracrine effects on JunB, Cyclin D1, p16INK4A, p18INK4C, CDK4 and CDK6 expressions in physiological term villous explants. PDMSCs were isolated from physiological (n = 20) and PE (n = 24) placentae. Passage three normal and PE-PDMSC and conditioned media (CM) were collected after 48h. Physiological villous explants (n = 60) were treated for 72h with normal or PE-PDMSCs CM. Explants viability was assessed by Lactate Dehydrogenase Cytotoxicity assay. Cyclin D1 localization was evaluated by Immuofluorescence (IF) while JunB, Cyclin-D1 p16INK4A, p18INK4C, CDK4 and CDK6 levels were assessed by Real Time PCR and Western Blot assay. We reported significantly increased p16INK4A and p18INK4C expression in PE- relative to normal PDMSCs while no differences in CDK4 and CDK6 levels were detected. Explants viability was not affected by normal or PE-PDMSCs CM. Normal PDMSCs CM increased JunB, p16INK4 and p18INK4C and decreased Cyclin-D1 in placental tissues. In contrast, PE-PDMSCs CM induced JunB downregulation and Cyclin D1 increase in placental explants. Cyclin D1 IF staining showed that CM treatment targeted mainly the syncytiotrophoblast. We showed Cyclin D1-p16INK4A/p18INK4C altered pathway in PE-PDMSCs demonstrating an aberrant G1/S phase transition in these pathological cells. The abnormal Cyclin D1-p16INK4A/p18INK4C expression in explants conditioned by PE-PDMSCs media suggest a key contribution of mesenchymal cells to the altered trophoblast cell cycle regulation typical of PE pregnancies with fetal-placental compromise.

SUBMITTER: Nuzzo AM

PROVIDER: S-EPMC5283823 | biostudies-other | 2017 Jan

REPOSITORIES: biostudies-other

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Altered expression of G1/S phase cell cycle regulators in placental mesenchymal stromal cells derived from preeclamptic pregnancies with fetal-placental compromise.

Nuzzo Anna Maria AM Giuffrida Domenica D Masturzo Bianca B Mele Paolo P Piccoli Ettore E Eva Carola C Todros Tullia T Rolfo Alessandro A

Cell cycle (Georgetown, Tex.) 20161212 2

Herein, we evaluated whether Placental Mesenchymal Stromal Cells (PDMSCs) derived from normal and Preeclamptic (PE) placentae presented differences in the expression of G1/S-phase regulators p16INK4A, p18INK4C, CDK4 and CDK6. Finally, we investigated normal and PE-PDMSCs paracrine effects on JunB, Cyclin D1, p16INK4A, p18INK4C, CDK4 and CDK6 expressions in physiological term villous explants. PDMSCs were isolated from physiological (n = 20) and PE (n = ...[more]

PMID: 27937072

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Project description:BackgroundWorldwide, stillbirth is one of the leading causes of death. Altered fetal growth and placental abnormalities are the strongest and most prevalent known risk factors for stillbirth. The aim of this study was to identify patterns of association between placental abnormalities, fetal growth, and stillbirth.Methods and findingsPopulation-based case-control study of all stillbirths and a representative sample of live births in 59 hospitals in 5 geographic areas in the U.S. Fetal growth abnormalities were categorized as small (<10th percentile) and large (>90th percentile) for gestational age at death (stillbirth) or delivery (live birth) using a published algorithm. Placental examination by perinatal pathologists was performed using a standardized protocol. Data were weighted to account for the sampling design. Among 319 singleton stillbirths and 1119 singleton live births at ?24 weeks at death or delivery respectively, 25 placental findings were investigated. Fifteen findings were significantly associated with stillbirth. Ten of the 15 were also associated with fetal growth abnormalities (single umbilical artery; velamentous insertion; terminal villous immaturity; retroplacental hematoma; parenchymal infarction; intraparenchymal thrombus; avascular villi; placental edema; placental weight; ratio birth weight/placental weight) while 5 of the 15 associated with stillbirth were not associated with fetal growth abnormalities (acute chorioamnionitis of placental membranes; acute chorioamionitis of chorionic plate; chorionic plate vascular degenerative changes; perivillous, intervillous fibrin, fibrinoid deposition; fetal vascular thrombi in the chorionic plate). Five patterns were observed: placental findings associated with (1) stillbirth but not fetal growth abnormalities; (2) fetal growth abnormalities in stillbirths only; (3) fetal growth abnormalities in live births only; (4) fetal growth abnormalities in stillbirths and live births in a similar manner; (5) a different pattern of fetal growth abnormalities in stillbirths and live births.ConclusionsThe patterns of association between placental abnormalities, fetal growth, and stillbirth provide insights into the mechanism of impaired placental function and stillbirth. They also suggest implications for clinical care, especially for placental findings amenable to prenatal diagnosis using ultrasound that may be associated with term stillbirths.

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Project description:BackgroundDecreased fetal movements (DFM) are associated with fetal growth restriction and stillbirth, presumably linked through an underlying placental dysfunction. Yet, the role of placental pathology has received limited attention in DFM studies. Our main objective was to explore whether maternal perceptions of DFM were associated with placental pathology in pregnancies recruited from a low-risk total population.Methods/principal findingsPlacentas from 129 DFM and 191 non-DFM pregnancies were examined according to standardized macro- and microscopic protocols. DFM was defined as any maternal complaint of DFM leading to a hospital examination. Morphological findings were timed and graded according to their estimated onset and clinical importance, and classified in line with a newly constructed Norwegian classification system for reporting placental pathology. With our population-based approach we were unable to link DFM to an overall measure of all forms of placental pathology (OR 1.3, 95% CI 0.8-2.2, p = 0.249). However, placental pathology leading to imminent delivery could be a competing risk for DFM, making separate subgroup analyses more appropriate. Our study suggests a link between DFM and macroscopic placental pathology related to maternal, uteroplacental vessels, i.e. infarctions, placental lesions (intraplacental hematomas) and abruptions. Although not statistically significant separately, a compound measure showed a significant association with DFM (OR 2.4, 95%CI 1.1-5.0, p = 0.023). This association was strengthened when we accounted for relevant temporal aspects. More subtle microscopic materno-placental ischemic changes outside the areas of localized pathology showed no association with DFM (OR 0.5, 95%CI 0.2-1.4, p = 0.203). There was a strong association between placental pathology and neonatal complications (OR 2.9, 95% CI 1.6-5.1, p<0.001).ConclusionsIn our population-based study we were generally unable to link maternally perceived DFM to placental pathology. Some associations were seen for subgroups.

Dataset Information

Altered expression of G1/S phase cell cycle regulators in placental mesenchymal stromal cells derived from preeclamptic pregnancies with fetal-placental compromise.

Publications

Altered expression of G1/S phase cell cycle regulators in placental mesenchymal stromal cells derived from preeclamptic pregnancies with fetal-placental compromise.

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