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Published on: July 30, 2016
Novel genes associated with a placental phenotype in knockout mice also respond to cellular stressors in primary
Elif Kadife1, Alesia Harper1, Keegan Chien1
1Obstetric Diagnostics and Therapeutics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, 163 Studley Road, Heidelberg, 3084, Victoria, Australia; Mercy Perinatal, Mercy Hospital for Women Heidelberg, 163 Studley Road, Heidelberg, 3084, Victoria, Australia.
Introduction:
Placental insufficiency is a leading cause of intrauterine growth restriction, contributing to perinatal morbidity and mortality. The molecular regulation of placental development and what causes placental insufficiency is poorly understood. Recently, a panel of genes were found to cause significant placental dysmorphologies in mice with severely growth restricted off-spring. We aimed to assess whether these genes were also implicated in human intrauterine growth restriction.
Methods:
We explored the expression of nine genes in primary cytotrophoblast cells in hypoxic (n = 6) and glucose starvation (n = 5) conditions in vitro. We also explored whether the genes were dysregulated in intrauterine growth restricted human placental samples (n = 11), with (n = 20) or without preeclampsia compared to gestationally matched controls (<34 weeks gestation) (n = 17).
Results:
Hypoxic stress significantly upregulated the expressions of BRD2 (p = 0.0313), SMG9 (p = 0.0313) genes. In contrast, glucose starvation significantly suppressed Kif1bp (p = 0.0089) in primary cytotrophoblasts. The FRYL, NEK9, CHTOP, PSPH, ATP11A, HM13 genes did not change under hypoxia or glucose starvation conditions. The expression of these genes was not altered in placenta from patients with intrauterine growth restriction, compared to gestationally matched controls.
Discussion:
We demonstrate that some of the genes that cause a placental phenotype in mice, respond to hypoxic and glucose mediated stress in human cytotrophoblast isolations. Despite this, they are unchanged in placenta from patients with intrauterine growth restriction. Therefore, dysregulation of these genes is less likely to contribute to preterm intrauterine growth restriction in humans.
Insights
Genes implicated in mouse placental issues show varied responses to stress in human cells but are not altered in human intrauterine growth restriction, suggesting they don't cause this condition.
Area of Science:
- Reproductive biology
- Developmental biology
- Genetics
Background:
- Placental insufficiency is a major cause of intrauterine growth restriction (IUGR), leading to significant perinatal complications.
- The molecular mechanisms underlying placental development and insufficiency remain poorly understood.
- Previous studies identified genes causing placental abnormalities in mice with IUGR offspring.
Purpose of the Study:
- To investigate the role of specific genes, identified in mouse models, in human intrauterine growth restriction.
- To determine if these genes are dysregulated in human placental tissues affected by IUGR.
Main Methods:
- Gene expression analysis was performed on primary human cytotrophoblast cells under hypoxic and glucose-deprived conditions in vitro.
- Gene expression was also assessed in human placental samples from IUGR pregnancies (with and without preeclampsia) and compared to controls.
Main Results:
- Hypoxia upregulated BRD2 and SMG9 expression, while glucose starvation suppressed Kif1bp expression in human cytotrophoblasts.
- The expression of FRYL, NEK9, CHTOP, PSPH, ATP11A, and HM13 genes remained unchanged under these stress conditions.
- No significant alterations in the expression of the studied genes were found in placentas from human IUGR cases compared to controls.
Conclusions:
- While some genes identified in mouse placental models respond to cellular stress in human cytotrophoblasts, their unaltered expression in human IUGR placentas suggests they are unlikely to be major contributors to preterm IUGR in humans.
