Reversal of gene dysregulation in cultured cytotrophoblasts reveals possible causes of preeclampsia

Zhou, Yan; Gormley, Matthew; Hunkapiller, Nathan; Kapidzic, Mirhan; Stolyarov, Yana; Feng, Victoria; Nishida, Masakazu; Drake, Penelope M.; Bianco, Katherine; Wang, Fei; McMaster, Michael; Fisher, Susan J.

doi:10.1172/jci72817

Cited by 18 publications

(20 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Targeted analyses of particular molecular families, such as the vascular-type adhesion molecules that are up-regulated as the extravillous CTBs enter the uterine wall, revealed focal defects in differentiation (8). These results were confirmed and augmented by global transcriptional profiling of CTBs isolated from the placentas of affected pregnancies as they differentiated along the invasive pathway over a period of 48 h in culture (9). The surprising finding that the abnormal pattern of gene expression autocorrected to control levels by the end of the culture period pointed to a potentially important role for paracrine effectors.…”

mentioning

confidence: 74%

Defective decidualization during and after severe preeclampsia reveals a possible maternal contribution to the etiology

Garrido-Gómez

Domı́nguez

Quiñonero

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

251

193

View full text Add to dashboard Cite

In preeclampsia (PE), cytotrophoblast (CTB) invasion of the uterus and spiral arteries is often shallow. Thus, the placenta’s role has been a focus. In this study, we tested the hypothesis that decidual defects are an important determinant of the placental phenotype. We isolated human endometrial stromal cells from nonpregnant donors with a previous pregnancy that was complicated by severe PE (sPE). Compared with control cells, they failed to decidualize in vitro as demonstrated by morphological criteria and the analysis of stage-specific antigens (i.e., IGFBP1, PRL). These results were bolstered by global transcriptional profiling data that showed they were transcriptionally inert. Additionally, we used laser microdissection to isolate the decidua from tissue sections of the maternal–fetal interface in sPE. Global transcriptional profiling revealed defects in gene expression. Also, decidual cells from patients with sPE, which dedifferentiated in vitro, failed to redecidualize in culture. Conditioned medium from these cells failed to support CTB invasion. To mimic aspects of the uterine environment in normal pregnancy, we added PRL and IGFBP1, which enhanced invasion. These data suggested that failed decidualization is an important contributor to down-regulated CTB invasion in sPE. Future studies will be aimed at determining whether this discovery has translational potential with regard to assessing a woman’s risk of developing this pregnancy complication.

show abstract

mentioning

confidence: 74%

Defective decidualization during and after severe preeclampsia reveals a possible maternal contribution to the etiology

Garrido-Gómez

Domı́nguez

Quiñonero

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

251

193

View full text Add to dashboard Cite

show abstract

“…Previously, we showed that the placenta and placental bed were essentially normal in nPTB. 17 Subsequently, this study design, which compared gene expression in sPE vs nPTB, enabled us to pinpoint changes in placental gene expression that are specific to the former syndrome 13,14 rather than attributable to alterations that occur with advancing gestational age. 28 Gene ontology analyses revealed the many biologic processes that sPE impacted in each trophoblast subtype that was profiled (Figure 2).…”

Section: Global Transcriptional Profiling Of Trophoblast Subtypes (Spmentioning

confidence: 99%

“…To date, these studies have focused on chorionic villi, 11,12 the maternal-fetal interface, 13 or purified cytotrophoblasts as they differentiate along the invasive pathway in vitro. 14 These studies have the advantage of being unbiased therefore enabling the de novo discovery of misregulated genes.…”

mentioning

confidence: 99%

Preeclampsia: novel insights from global RNA profiling of trophoblast subpopulations

Gormley

Ona

Kapidzic

et al. 2017

American Journal of Obstetrics and Gynecology

Self Cite

View full text Add to dashboard Cite

BACKGROUND:The maternal signs of preeclampsia, which include the new onset of high blood pressure, can occur because of faulty placentation. We theorized that transcriptomic analyses of trophoblast subpopulations in situ would lend new insights into the role of these cells in preeclampsia pathogenesis. OBJECTIVE: Our goal was to enrich syncytiotrophoblasts, invasive cytotrophoblasts, or endovascular cytotrophoblasts from the placentas of severe preeclampsia cases. Total RNA was subjected to global transcriptional profiling to identify RNAs that were misexpressed compared with controls. STUDY DESIGN: This was a cross-sectional analysis of placentas from women who had been diagnosed with severe preeclampsia. Gestational age-matched controls were placentas from women who had a preterm birth with no signs of infection. Laser microdissection enabled enrichment of syncytiotrophoblasts, invasive cytotrophoblasts, or endovascular cytotrophoblasts. After RNA isolation, a microarray approach was used for global transcriptional profiling. Immunolocalization identified changes in messenger RNA expression that carried over to the protein level. Differential expression of noneprotein-coding RNAs was confirmed by in situ hybridization. A 2-way analysis of variance of non-coding RNA expression identified particular classes that distinguished trophoblasts in cases vs controls. Cajal body foci were visualized by coilin immunolocalization. RESULTS: Comparison of the trophoblast subtype data within each group (severe preeclampsia or noninfected preterm birth) identified many highly differentially expressed genes. They included molecules that are known to be expressed by each subpopulation, which is evidence that the method worked. Genes that were expressed differentially between the 2 groups, in a cell-typeespecific manner, encoded a combination of molecules that previous studies associated with severe preeclampsia and those that were not known to be dysregulated in this pregnancy

show abstract

“…Besides unfavorable immunological interactions of EVTs with uterine natural killer (uNK) cells (11), abnormal placental development and trophoblast differentiation are thought to contribute to the pathogenesis of gestational disorders. Indeed, CTBs isolated from preeclamptic placentae failed to appropriately differentiate into the invasive lineage in vitro and expressed an antimigratory gene signature (12,13).…”

mentioning

confidence: 99%

Notch1 controls development of the extravillous trophoblast lineage in the human placenta

Haider

Meinhardt

Saleh

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

122

144

View full text Add to dashboard Cite

Development of the human placenta and its different epithelial trophoblasts is crucial for a successful pregnancy. Besides fusing into a multinuclear syncytium, the exchange surface between mother and fetus, progenitors develop into extravillous trophoblasts invading the maternal uterus and its spiral arteries. Migration into these vessels promotes remodelling and, as a consequence, adaption of blood flow to the fetal–placental unit. Defects in remodelling and trophoblast differentiation are associated with severe gestational diseases, such as preeclampsia. However, mechanisms controlling human trophoblast development are largely unknown. Herein, we show that Notch1 is one such critical regulator, programming primary trophoblasts into progenitors of the invasive differentiation pathway. At the 12th wk of gestation, Notch1 is exclusively detected in precursors of the extravillous trophoblast lineage, forming cell columns anchored to the uterine stroma. At the 6th wk, Notch1 is additionally expressed in clusters of villous trophoblasts underlying the syncytium, suggesting that the receptor initiates the invasive differentiation program in distal regions of the developing placental epithelium. Manipulation of Notch1 in primary trophoblast models demonstrated that the receptor promotes proliferation and survival of extravillous trophoblast progenitors. Notch1 intracellular domain induced genes associated with stemness of cell columns, myc and VE-cadherin, in Notch1−fusogenic precursors, and bound to themycpromoter and enhancer region at RBPJκ cognate sequences. In contrast, Notch1 repressed syncytialization and expression of TEAD4 and p63, two regulators controlling self-renewal of villous cytotrophoblasts. Our results revealed Notch1 as a key factor promoting development of progenitors of the extravillous trophoblast lineage in the human placenta.

show abstract

Reversal of gene dysregulation in cultured cytotrophoblasts reveals possible causes of preeclampsia

Cited by 18 publications

References 0 publications

Defective decidualization during and after severe preeclampsia reveals a possible maternal contribution to the etiology

Defective decidualization during and after severe preeclampsia reveals a possible maternal contribution to the etiology

Preeclampsia: novel insights from global RNA profiling of trophoblast subpopulations

Notch1 controls development of the extravillous trophoblast lineage in the human placenta

Contact Info

Product

Resources

About