Abstract/Details

Human trophoblast differentiation and invasion during normal pregnancy and preeclampsia


2011 2011

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Abstract (summary)

This work stems from our group's interest in identifying the mechanisms that govern placental function in normal human pregnancy and in pregnancy complications. Cytotrophoblasts (CTBs) carry out many of the placenta's most important functions. CTBs in contact with the uterus differentiate and subsequently invade the uterine stroma and blood vessels, a process that anchors the placenta to the uterus and redirects maternal blood toward the embryo/fetus. During differentiation/invasion, CTBs undergo phenotypic changes that result in vascular mimicry and display a marked arterial tropism. However, in preeclampsia (PE) CTB differentiation goes awry, and CTB invasion, particularly the arterial component, is shallow.

First, we theorized that molecules involved in arterial differentiation/function might play a role during vascular invasion. We found that expression of Notch family members, which play important roles during arterial differentiation, was extensively modulated during human CTB invasion. Inhibition reduced CTB invasion and expression of an arterial marker. Using mouse models, we confirmed that Notch activity was highest in artery-associated trophoblasts. Analysis of mouse trophoblast stem cell differentiation in vitro suggested that Notch2 played an important role in remodeling the uterine arterioles in this species. Conditional deletion of Notch2 in invasive trophoblast lineages highlighted its central importance in coordinating increases in utero-placental blood flow; trophoblast invasion of maternal arterioles failed, the blood canals that supply the placenta were smaller, and placental perfusion was decreased. Lastly, we asked whether defects in CTB expression of Notch family members were evident in PE. An absence of endovascular TB expression of the Notch ligand, JAG1, was frequently observed, suggesting that failures in Notch signaling are an important part of the pathogenesis of this condition.

Second, we theorized that dysregulated CTB differentiation underlies preeclampsia. To test this hypothesis, we compared gene expression in differentiating CTBs derived from normal and PE placentas. Molecules known to be dysregulated in PE as well as novel candidate regulators were differentially expressed. Of these targets, we performed an expanded functional analysis on SEMA3B. The results helped to explain alterations in CTB and endothelial cell (EC) phenotypes that are commonly observed in PE.

Last, we designed and tested high throughput methods to profile miRNA expression. These were applied in studies we initiated to probe the molecular mechanisms involved trophoblast differentiation and to identify novel serum biomarkers associated with PE. First, we performed experiments to optimize our experimental workflow, in which we measured the quantitative sensitivity of the Taqman miRNA expression assays in a variety of experimental conditions. Next, we identified miRNAs expressed by differentiating CTBs from normal and preeclamptic pregnancies. Lastly, we found many miRNAs that were differentially expressed in serum samples from women who experienced normal pregnancies or those complicated by PE. We believe that the results of the aforementioned experiments will enable many new research directions in the study of the maternal-fetal vascular interactions that occur during normal placentation and in pathological pregnancies.

Indexing (details)


Subject
Molecular biology;
Developmental biology
Classification
0307: Molecular biology
0758: Developmental biology
Identifier / keyword
Health and environmental sciences; Biological sciences; Endovascular invasion; Placenta; Preeclampsia; Pregnancy; Trophoblast
Title
Human trophoblast differentiation and invasion during normal pregnancy and preeclampsia
Author
Hunkapiller, Nathan
Number of pages
168
Publication year
2011
Degree date
2011
School code
0034
Source
DAI-B 72/06, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9781124570426
Advisor
Fisher, Susan J.
Committee member
Wang, Rong; Werb, Zena
University/institution
University of California, San Francisco
Department
Biomedical Sciences
University location
United States -- California
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3449591
ProQuest document ID
862877895
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/862877895
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