Abstract
BackgroundAbnormal trophoblast differentiation and function is the basis of many placenta-based pregnancy disorders, including pre-eclampsia and fetal growth restriction. PPARγ, a ligand-activated nuclear receptor, plays essential roles in placental development; null murine embryos die at midgestation due to abnormalities in all placental layers, in particular, small labyrinth and expanded giant cell layer. Previous studies have focused mostly on the role of PPARγ in trophoblast invasion. Based on the previously reported role of PPARγ in preadipocyte differentiation, we hypothesized that PPARγ also plays a pivotal role in trophoblast differentiation. To test this hypothesis, we report derivation of wild-type and PPARγ-null trophoblast stem (TS) cells.Methodology/Principal FindingsPPARγ-null TS cells showed defects in both proliferation and differentiation, specifically into labyrinthine trophoblast. Detailed marker analysis and functional studies revealed reduced differentiation of all three labyrinthine lineages, and enhanced giant cell differentiation, particularly the invasive subtypes. In addition, rosiglitazone, a specific PPARγ agonist, reduced giant cell differentiation, while inducing Gcm1, a key regulator in labyrinth. Finally, reintroducing PPARγ into null TS cells, using an adenovirus, normalized invasion and partially reversed defective labyrinthine differentiation, as assessed both by morphology and marker analysis.Conclusions/SignificanceIn addition to regulating trophoblast invasion, PPARγ plays a predominant role in differentiation of labyrinthine trophoblast lineages, which, along with fetal endothelium, form the vascular exchange interface with maternal blood. Elucidating cellular and molecular mechanisms mediating PPARγ action will help determine if modulating PPARγ activity, for which clinical pharmacologic agonists already exist, might modify the course of pregnancy disorders associated with placental dysfunction.
Highlights
Placental dysfunction, caused by abnormalities in trophoblast differentiation and function, is associated with many pregnancy disorders, including intrauterine growth restriction and preeclampsia [reviewed in 1]
In WT trophoblast stem (TS) cell cultures, PPARc mRNA and protein were detected at very low levels in the undifferentiated state, but were strongly upregulated upon differentiation, with maximal expression observed at day 4 (Figures 1C and 1D)
While levels of PPARa were comparable between WT and null TS cells, PPARb/d was upregulated (1.5–2.5 fold by densitometry, normalized to bactin expression) in differentiated null cells compared to PPARc+/+ cells (Figure 1D); these changes in PPARa and PPARb/d protein levels were reflective of changes in their respective mRNA levels
Summary
Placental dysfunction, caused by abnormalities in trophoblast differentiation and function, is associated with many pregnancy disorders, including intrauterine growth restriction and preeclampsia [reviewed in 1]. Genetically null mice revealed a surprising role for PPARc: namely its essential role in placental development [6,7] Since this discovery, additional studies have focused primarily on the effect of PPARc ligands in human trophoblast, revealing effects on both syncytiotrophoblast function [8] and trophoblast invasion [9]. PPARc, a ligand-activated nuclear receptor, plays essential roles in placental development; null murine embryos die at midgestation due to abnormalities in all placental layers, in particular, small labyrinth and expanded giant cell layer. Based on the previously reported role of PPARc in preadipocyte differentiation, we hypothesized that PPARc plays a pivotal role in trophoblast differentiation To test this hypothesis, we report derivation of wild-type and PPARc-null trophoblast stem (TS) cells
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